Lub luag haujlwm ntawm GTPase-activating Proteins hauv Kev Tswj Xyuas Cell Tuag Thiab Tumor Immunity
May 05, 2023
Abstract
GTPase-activating protein (GAP) yog tus tswj tsis zoo ntawm GTPase protein uas xav tias yuav txhawb kev hloov pauv ntawm GTPase-GTP daim ntawv mus rau GTPase-GDP daim ntawv. Raws li nws lub peev xwm los tswj GTPase cov proteins thiab lwm qhov chaw, GAPs ncaj qha lossis tsis ncaj qha cuam tshuam rau ntau yam txheej txheem ntawm tes. Peb tau tshuaj xyuas cov pov thawj uas twb muaj lawm ntawm GAPs tswj hwm kev tuag ntawm tes (RCD), feem ntau yog apoptosis thiab autophagy, nrog rau qee qhov tshiab RCDs, nrog rau kev saib xyuas tshwj xeeb rau lawv cov koom haum nrog cov kab mob, tshwj xeeb tshaj yog mob qog noj ntshav. Peb kuj tau txiav txim siab tias GAPs tuaj yeem cuam tshuam rau kev tiv thaiv qog nqaij hlav thiab sim txuas GAPs, RCD, thiab qog kev tiv thaiv kab mob. Kev nkag siab tob dua ntawm GAPs rau kev tswj cov txheej txheem no tuaj yeem ua rau kev tshawb pom ntawm cov hom phiaj kho mob tshiab kom tsis txhob muaj kab mob ntawm tes los yog kho mob qog noj ntshav tuag.
Regulatory cell tuag yog hais txog kev tuag ntawm ib chav kawm ntawm kev tswj cov hlwb hauv lub cev tiv thaiv kab mob, yog li tswj kev siv zog thiab lub sijhawm ntawm kev tiv thaiv kab mob. Regulatory cells muaj xws li tswj T hlwb thiab tswj B hlwb, thiab lwm yam, uas yog ib qho tseem ceeb heev rau kev tswj lub homeostasis ntawm lub cev tiv thaiv kab mob. Muaj kev sib raug zoo ntawm kev tswj hwm cell tuag thiab kev tiv thaiv kab mob. Kev tswj hwm ntawm tes tuag tuaj yeem cuam tshuam qhov kev siv zog thiab lub sijhawm ntawm kev tiv thaiv kab mob thiab yog li theem ntawm kev tiv thaiv. Ntawm qhov tod tes, tswj kev tuag ntawm tes tuaj yeem ntxiv dag zog rau lub cev tiv thaiv kab mob thiab txhawb kev tshem tawm cov kab mob. Ntawm qhov tod tes, kev tswj hwm cell tuag ntau dhau tuaj yeem ua rau tsis muaj zog tiv thaiv kab mob, ua rau muaj kev cuam tshuam rau kev kis kab mob thiab kab mob autoimmune. Hauv cov ntsiab lus, kev tswj hwm cell tuag muaj feem cuam tshuam nrog kev tiv thaiv kab mob. Kev tswj hwm kev tuag ntawm tes tsim nyog tuaj yeem ntxiv dag zog rau lub cev tiv thaiv kab mob thiab txhawb kev tshem tawm cov kab mob, tab sis kev tswj hwm ntawm tes tuag ntau dhau kuj tseem tuaj yeem ua rau lub cev tsis muaj zog, ua rau lub cev raug mob thiab tshwm sim ntawm cov kab mob autoimmune. Yog li ntawd, peb yuav tsum xyuam xim rau kev txhim kho kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv. Cistanche yog nplua nuj nyob rau hauv ntau yam tshuaj antioxidant, xws li vitamin C, vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals, txo oxidative kev nyuaj siab, thiab txhim kho kev tiv thaiv. tiv thaiv kab mob.
Nyem cistanche deserticola ntxiv
Ntsiab lus:
GTPase-activating proteins, tswj cell tuag, qog tiv thaiv kab mob.
Taw qhia
Tib neeg Ras superfamily (monomeric GTPases) ntawm me me guanosine triphosphatases (me GTPases) muaj ntau dua 150 tus tswv cuab [1] thiab feem ntau muab faib ua tsib tsev neeg tseem ceeb: Ras, Rho, Rab, Arf, thiab Ran tsev neeg [2]. Lawv cuam tshuam nrog ntau yam txheej txheem ntawm tes, suav nrog cov teeb liab kis tau tus mob, thauj khoom, thiab kev tsim kho ntawm cytoplasmic skeleton [3]. Me GTPases muaj ob lub xeev sib txawv thiab lub voj voog rov qab los ntawm lawv.
Hauv lub xeev qhib, lawv raug khi rau GTP, thiab qhov sib txawv yog qhov tseeb rau GDP. Lub xeev kev hloov pauv no yog tswj hwm los ntawm peb tus tswj hwm: guanine nucleotide exchange factor (GEFs), guanine nucleotide dissociation inhibitors (GDIs), thiab GTPase activating proteins (GAPs) [4]. Ntawm cov no, GEFs yog qhov zoo uas ua rau GTPase los ntawm kev txhawb nqa kev khi rau GTP, thaum GDIs thiab GAPs yog ob qho tib si tsis zoo uas ua rau GTPase tsis ua haujlwm los ntawm sequestering thiab hydrolyzing GTP, feem [3, 4].
GAPs yog ntau yam qauv domain proteins (Fig. 1) uas muaj li ntawm 50 mus rau 250 kDa loj [5]. Ua ke nrog Ras superfamily ntawm GTPases, GAPs kuj tuaj yeem muab faib ua tsib tsev neeg tseem ceeb: Ras-GAPs, RhoGAPs, Rab-GAPs, Arf-GAPs, thiab Ran-GAPs tsev neeg. Hauv kev sib piv rau GAPs rau Ras superfamily, chav kawm ntawm GAPs, hu ua regulators ntawm G protein signaling (RGSs), ua rau heterotrimeric G proteins [5, 6]. Ib zaug nyob rau hauv GDP-bound conformation, GAPs feem ntau tuaj yeem txiav tawm qhov sib thooj downstream signaling cascades los ntawm hydrolyzing GTP. GTP cov tshuaj tiv thaiv hydrolysis qeeb heev, tab sis GAPs tuaj yeem ua kom nrawm nrawm ntawm cov kauj ruam los ntawm ntau qhov kev txiav txim siab kom nce qhov hydrolysis. Thaum lub sij hawm RasGTP hydrolysis, ib txwm GAPs ntxig arginine ntiv tes los yog asparagine ntiv tes xoo rau hauv cov nucleotide-binding groove ntawm lub hom phiaj GTPase los txhawb hydrolysis [7, 8], thaum RGS proteins ncaj qha khi rau cov nquag G subunits ntawm G-protein coupled receptor. (GPCR) rau induce hydrolysis [6].
Physiologically, cell tuag yog ib qho homeostatic mechanism uas tswj thiab tswj cov kev ua haujlwm thiab qhov loj ntawm cov ntaub so ntswg thiab kabmob. Qhov txawv txav ntawm kev tuag ntawm tes (ACD), qhov tshwm sim ntawm kev cuam tshuam ib puag ncig sab nraud, kev tswj hwm ntawm tes tuag (RCD), yuav tsum tau ua rau lub cev lossis cov kab mob pathological uas ua kom muaj cov kab mob endogenous genetic encoded molecular structured signaling cascades thiab mechanisms, uas tuaj yeem cuam tshuam los ntawm caj ces. los yog tshuaj pharmacological. RCD tuaj yeem faib ua ob hom tswv: apoptotic thiab nonapoptotic. Apoptosis yog hom kab mob ntau tshaj plaws ntawm kev tuag ntawm tes (PCD), thaum lwm pawg tseem ceeb ntawm nonapoptotic RCD, uas suav nrog necroptosis, autophagy, mitotic catastrophe, pyroptosis, ferroptosis, methuosis, proptosis, parthanatos, lysosome-dependent cell tuag, entosis, thiab oncosis, kuj tau txais kev saib xyuas [9, 10].
Cov kev sib txawv ntawm cov cell tuag no txawv los ntawm cov kev hloov morphological thiab biochemical yam ntxwv tshwm sim los ntawm lawv txoj kev tuag stimuli, tab sis qee hom kev tuag ntawm tes tsis muaj kev ywj pheej ntawm lwm tus, nrog rau qee qhov kev sib tshuam ntawm cov yam ntxwv molecular, xws li apoptosis thiab autophagic cell tuag [11 ]. Tsis hais txog cov kev cai ntawm kev tuag ntawm tes, cov qog nqaij hlav qog noj ntshav muaj sia nyob thaum tsis xav tau, feem ntau, los ntawm kev tsim cov noob caj noob ces hloov pauv lossis hloov kho epigenetic uas cuam tshuam rau kev sib kis ntawm cov xov tooj ntawm tes tuag kom hla RCD.
Kev tswj hwm ntawm GTPase kev ua los ntawm GAPs ua rau muaj kev hloov pauv ntawm cov teeb liab, tshwj xeeb hauv kev loj hlob ntawm tes, kev loj hlob, thiab kev tuag, thiab peb tau tsim qhov peb tuaj yeem soj ntsuam raws li RCD thiab qog kev tiv thaiv kab mob los tshawb txog cov kev sib txuas ntawm peb. Hauv kev tshuaj xyuas no, peb yuav xub tham txog kev nkag siab txog cov txheej txheem molecular ntawm GAPs rau cov RCDs sib txawv, piv txwv nrog ntau tus neeg ua piv txwv (Table 1), thiab thaum kawg, lub hom phiaj tseem ceeb yuav raug muab tso rau hauv kev tswj hwm qog noj ntshav los ntawm GAPs. . Los ntawm kev sau cov kev paub no, peb yuav piav qhia ntxiv txog qhov cuam tshuam ntawm pathophysiological ntawm GAP kev tswj hwm ntawm cov txheej txheem no thiab qhia txog kev cog lus kho mob qog noj ntshav hauv qhov pom ntawm cov kev tshawb pom tshiab no.
Apoptosis
Apoptosis yog ib hom PCD thiab tseem hu ua 'shrinkage necrosis' [12] vim yog cov yam ntxwv morphological ntawm chromatin condensation thiab cell shrinkage (pyknosis). Tsis tas li ntawd, nws cov yam ntxwv muaj xws li DNA fragmentation (karyorrhexis), apoptosome tsim, thiab membrane blebbing [9]. Ob txoj kev taw qhia kev ua rau apoptosis: ib txoj hauv kev yog txoj hauv kev, uas yog vim muaj kev hloov pauv hauv mitochondrial membrane muaj peev xwm thiab txheej txheej membrane permeability thiab ces txhawb kev tso tawm ntawm mitochondrial proteins xws li cytochrome c, li no activating caspase 3 thiab tsim apoptosomes [13] ]. Cov txheej txheem no yog tswj hwm los ntawm BCL-2 tsev neeg cov proteins, feem ntau yog cov proteins proapoptotic (BAX, BAK, BIM, PUMA, thiab BID) thiab cov proteins antiapoptotic (BCL-2, BCL-XL, thiab MCL1) [ 14] ib. Lwm txoj hauv kev yog txoj kev extrinsic apoptosis uas tau pib los ntawm kev tuag-inducing signaling complex (DISC) thiab tuag receptors (cell membrane protein), xws li Fas, qog necrosis factor (TNF) receptors, thiab TNF-txog apoptosis-inducing ligand. (TRAIL) receptors, uas thaum kawg qhib lub caspase protease tsev neeg, cov executors ntawm cell apoptosis, thiab induce cell apoptosis [13, 15].
Cov kab mob Apoptosis muaj feem cuam tshuam nrog kev tshwm sim thiab kev loj hlob ntawm cov kab mob autoimmune, kab mob neurodegenerative, thiab qog. Piv txwv li, cov qog nqaij hlav cancer feem ntau muaj cov yam ntxwv ntawm inhibiting apoptosis kom ntseeg tau tias tsis muaj kev loj hlob.
Cov kev tshawb fawb tshiab tau qhia tias GAPs muaj feem cuam tshuam nrog kev mob apoptotic (Fig. 2). Qee GAPs tuaj yeem txhawb nqa apoptosis ntawm cov qog hlwb los tiv thaiv kab mob. p120RasGAP, tus tswj hwm ntawm G-protein signaling 3 (RGS3), tshem tawm hauv daim siab mob cancer 1 (DLC1), DOC-2/ DAB2 interacting protein (DAB2IP), thiab STARD13 yog cov piv txwv zoo vim tias tsib GAPs tuaj yeem cuam tshuam qhov sib npaug ntawm antiapoptotic proteins thiab proapoptotic proteins thiab / los yog cov teeb meem coj mus rau induce apoptosis. p120RasGAP (tseem hu ua RASA1), classical GAP ntawm RAS, induces Ras-dependent tumorigenicity thaum nws cov kev cai transcriptional repressed. Sorafenib, raws li tus neeg sawv cev tsom rau hauv hepatocellular carcinoma (HCC), tuaj yeem ua rau apoptosis ntawm cov qog hlwb. Cov kev tshawb fawb tau pom tias nws txoj hauv kev tseem ceeb nce qib ntawm p120RasGAP rau nws cov txiaj ntsig kho mob los ntawm kev txhawb nqa cov phosphorylation ntawm pituitary homeobox 1 (PITX1) kom nws cov lus qhia thiab kev ruaj ntseg [16]. Txawm li cas los xij, seb apoptosis tuaj yeem ua tiav tau zoo nyob ntawm qib ntawm kev taw qhia txoj hauv kev. Caspase-3 yog qhov ua haujlwm me me, uas tawm tsam apoptosis thiab txhawb nqa txoj sia nyob ntawm tes los ntawm kev txiav p120RasGAP ua ob ntu; nws cov N-terminal fragment activates PI3k/Akt txoj kev, thiab tsuas yog lub hyperactivation ntawm caspase yuav txhawb apoptotic cell tuag [17, 18].
Hauv HCC, qhov kev qhia ntawm RGS3 yog cuam tshuam los ntawm oncogenic lncRNA HOXD-AS1, uas txo qis mRNA qib ntawm RGS3 thiab ua rau MEK / ERK signaling txoj hauv kev los tiv thaiv apoptosis [19]. HOXD-AS1 tseem txhawb nqa qhov kev qhia ntawm ARHGAP11A (ib RhoGAP) thiab ua rau muaj kev cuam tshuam ntawm metastasis los ntawm kev ua haujlwm ua ib qho kev sib tw endogenous RNA (ceRNA) thiab repressing miR19 [19]. Zoo ib yam li HOXD-AS1, STARD13 (DLC2, a RhoGAP) 3'UTR ua raws li ceRNA thiab nce Bcl-2 hloov pauv qhov tshwm sim (BMF) qhia los ntawm kev sib tw nrog miR-125b hauv mob qog noj ntshav.
Lub caij no, STARD13 3'UTR tuaj yeem txhawb kev sib cuam tshuam ntawm BMF/Bcl-2 kom tso Bax thiab cytochrome c los qhib txoj hauv kev ntawm apoptosis [20]. DLC1 thiab DAB2IP ncaj qha cuam tshuam rau txoj hauv kev sib raug thiab lub hom phiaj cov protein kom ntxias apoptosis. Piv txwv li, DLC1 (a RhoGAP) deregulates qhov kev qhia ntawm TNFAIP3/A20 thiab upregulates qhov kev qhia ntawm BCL211/BIM thiab caspase-3 induce cell tuag los ntawm inactivating NF-кB signaling nyob rau hauv angiosarcoma [21]. Lub DAB2IP cov txiaj ntsig ntawm kev txhawb nqa apoptosis cuam tshuam nrog ntau txoj hauv kev qhia hauv kev mob qog noj ntshav [22]. Hauv kev mob qog noj ntshav prostate (PCa), DAB2IP muaj ob lub luag haujlwm hauv kev cuam tshuam apoptosis. Ua ntej, DAB2IP ncaj qha cuam tshuam nrog STAT3 thiab inhibits nws cov phosphorylation (tyrosine 705 thiab serine 727) thiab transactivation, yog li cuam tshuam qhov sib npaug ntawm cov noob pro-apoptotic (Bax) thiab anti-apoptotic genes (muaj sia nyob, Bcl-2 thiab Bcl. -xL) thiab txhawb nqa apoptosis. Thib ob, DAB2IP qhib txoj hauv kev, suav nrog kev cuam tshuam ntawm mitochondrial membrane muaj peev xwm thiab tso tawm cytochrome c, Omi / HtrA2, thiab Smac, thaum kawg ua kom lub caspase cascade [23].
RACGAP1 tuaj yeem txhawb cov metastasis thiab kev loj hlob ntawm qog noj ntshav los ntawm inhibiting apoptosis. RACGAP1 ua rau G proteins me me ntawm Rho tsev neeg, txhawb nqa GTP hydrolysis thiab tswj CDC42 thiab RAC1. Kev qhia thiab kev ruaj ntseg ntawm RACGAP1 yog cuam tshuam los ntawm STAT3 thiab epithelial cell transforming sequence 2 (ECT2). Hauv HCC, STAT3, ib qho kev hloov pauv ntawm RACGAP1, tuaj yeem txhim kho qhov kev qhia ntawm RACGAP1, thiab tom qab ntawd, RACGAP1 txo cov Hippo signaling txoj hauv kev los ntawm kev tsub zuj zuj ntawm F-actin los qhib cov transcription coactivator yes-associated protein (YAP). Nrog YAP, qhov kev hloov pauv ntawm nucleoporin translocated promoter cheeb tsam (TPR) yog upregulated. TPR nyob rau hauv lem tuaj yeem tswj cov phosphorylation thiab localization ntawm RACGAP1 nyob rau hauv nruab nrab spindle. Raws li qhov tshwm sim, apoptosis yog inhibited thaum kev loj hlob ntawm cov qog hlwb raug txhawb [24]. ECT2, tus neeg sawv cev catalytic ntawm guanine nucleotide pauv ntawm GTPases me me [25], cuam tshuam nrog RacGAP1. Hauv HCC, ntawm ib sab, ECT2 txhawb nqa RacGAP1 protein ruaj khov, thiab ntawm qhov tod tes, RacGAP1 txhawb nqa ECT2-kev sib kho RhoA ua kom muaj zog thiab HCC cell metastasis [26]. Hauv basal-zoo li mob qog noj ntshav mis (BLBC), knockdown RACGAP1 hlwb kuj tau pom tias ua tsis tiav hauv cytokinesis thiab ua rau pib ntawm apoptosis [27].
Muaj tseeb tiag, GAPs kuj ua lub luag haujlwm tseem ceeb hauv lwm yam kab mob apoptosis tshwj tsis yog mob qog noj ntshav. Untimely thiab tsis tsim nyog apoptosis yuav txhawb nqa qhov tshwm sim ntawm cov kab mob plawv. Xya caum feem pua ntawm cov neeg mob capillary malformation-arteriovenous malformation cov neeg mob tam sim no nrog inactivated mutations nyob rau hauv RASA1 noob. Feem ntau, raws li kev ua haujlwm ntawm cleaved N-terminal fragment ntawm RASA1 nyob rau hauv kev sib kho los tiv thaiv apoptosis, RASA1 deficiency ua rau apoptosis ntawm lymphatic hlab ntsha (LV) endothelial hlwb, ua rau lub impaired tsim ntawm LV li qub [28].
Tsis tas li ntawd, RGS5 tsis tsuas yog tswj hwm kev ua haujlwm ntawm proapoptotic proteins, antiapoptotic proteins, thiab caspase-3 tab sis kuj inhibits JNK1/2 thiab p38 cov cim qhia txoj hauv kev los tiv thaiv apoptosis ntawm cardiomyocytes, uas muaj nyob rau hauv myocardial ischemia-reperfusion [29 ]. Tsis tsim nyog apoptosis kuj muaj feem xyuam rau cov kab mob neurological thiab optic neuropathy. Cov kws tshawb fawb qhia tias kev tshaj tawm ntawm DAB2IP, uas muaj lub npe tshiab apoptosis teeb liab tswj kinase 1-interacting protein-1, tuaj yeem txhawb txoj kev loj hlob ntawm Alzheimer's kab mob los ntawm kev sib kho -amyloid-induced apoptosis ntawm cerebral endothelial hlwb, thaum lub sij hawm overexpression ntawm TBC1D17 yuav txhawb retinal cell tuag kom ua tau optic neuropathy [30, 31].
Hauv cov ntsiab lus, GAPs tau hais los saum no cuam tshuam nrog lawv lub hom phiaj cov protein lossis cov cim qhia txoj hauv kev los qhib lossis inhibit apoptotic signaling pathways thiab cuam tshuam apoptosis, yog li cuam tshuam rau kev loj hlob ntawm tus kab mob. Tsis tu ncua, cov kws tshawb fawb tau mob siab rau cov txheej txheem thiab cov tswv yim kho mob ntawm cov qog. Ntawm no, peb qhia qee qhov GPAs uas cuam tshuam rau apoptosis los qhia cov txheej txheem pathological thiab txhim kho cov nyhuv kho ntawm cov qog. Tau kawg, GAP kev tshawb fawb tseem qhia txog cov txheej txheem tshwj xeeb ntawm lwm cov txheej txheem pathological los ua kom peb nkag siab zoo txog kev tsim qauv thiab pab peb txhim kho kev kho kom zoo rau lub hom phiaj tshwj xeeb.
Tsis-apoptotic RCD
Tshooj lus no tsis yog tsuas yog autophagy-dependent cell tuag los piav qhia txog kev koom tes nrog GAPs tab sis tseem muaj cov ntaub ntawv tshiab ntawm kev tuag ntawm tes, xws li ferroptosis, pyroptosis, thiab lwm yam tsis raws cai (Fig. 3).
Autophagy-dependent cell tuag
Yuav kom tswj tau peb lub cev homeostasis thiab kev noj qab haus huv, nws yog ib qho tsim nyog yuav tau qhib autophagy kom tshem tawm cov khoom siv tsis zoo thiab tsis zoo ntawm cov cell. Autophagy yog ib qho tseem ceeb, kev txuag, thiab cov txheej txheem ntawm tes uas ib txwm muab faib ua ob peb kauj ruam: induction ntawm phagophores, tsim ntawm autophagosomes thiab autolysosomes, thiab degradation thiab recirculation ntawm cov ntsiab lus luminal. Cov yam ntxwv tseem ceeb yog cov qauv membrane tshwj xeeb, suav nrog phagophores, autophagosomes, thiab autolysosomes. Autophagy yog suav tias yog ib qho kev ciaj sia ntawm tes, tab sis thaum autophagy yog overactivated dhau ntawm lub peev xwm ntawm tes, nws ua rau kev tuag ntawm tes, hu ua autophagy-dependent cell death (ADCD). Kev txheeb xyuas ntawm ADCD yuav tsum muaj cov yam ntxwv ntawm kev nce qib ntawm kev ua haujlwm autophagic thiab tsis suav nrog kev tuag ntawm tes vim yog lwm cov ntaub ntawv, thiab nws tuaj yeem hloov kho los ntawm caj ces thiab / lossis cov tshuaj pharmacological inhibition ntawm autophagy yam [32].
Txawm li cas los xij, lub tswv yim ntawm ADCD tseem muaj kev tsis sib haum xeeb. Ntawm qhov tod tes, qhov muaj nyob ntawm crosstalk ntawm autophagy thiab lwm yam RCDs, xws li apoptosis, ua rau nws nyuaj rau kev txhais ADCD raws li cov txheej txheem kev tuag ntawm tes tsuas yog los ntawm cov cim molecular thiab morphological, thiab ntawm qhov tod tes, qhov pib los faib cov neeg tuag. thiab nonlethal autophagy yog qhov nyuaj los txiav txim [33, 34]. Lub luag haujlwm ntawm autophagy hauv cov qog tuaj yeem yog ob sab. Txawm hais tias qhov poob ntawm autophagy txhawb cov qog nqaij hlav hauv cov qauv nas, ntau cov pov thawj qhia tau tias autophagy tuaj yeem cuam tshuam cov qog nqaij hlav tshwj xeeb thiab pab cov qog cell metabolic ua haujlwm hauv cov khoom noj khoom haus-tso microenvironment, txhawb cov qog loj hlob [35, 36]. Nws tau raug pom tias qee cov tshuaj tiv thaiv kab mob, xws li resveratrol thiab arsenic trioxide, tuaj yeem ua rau ADCD [37–39], thiab ntxiv rau, ADCD tshwm sim hauv oncogenic Ras-expressing hlwb thaum tsis muaj lwm yam cotransformed noob [40], tab sis nws lub luag hauj lwm nyob rau hauv ntau yam qog tseem yuav tau tshawb nrhiav. Yog li ntawd, peb tsuas yog muab qee qhov kev taw qhia rau lub luag haujlwm ntawm GAPs hauv autophagy ntawm no.
Autophagosomes yog cov cim morphological ntawm autophagy, thaum autophagy (ATG) cov proteins uas muaj feem xyuam yog qhov tseem ceeb rau kev tsim autophagosome thiab yog cov cim molecular ntawm autophagy. RAB GTPases tuaj yeem tswj kev thauj mus los ntawm cov hlab ntsha hauv lub cev [41] thiab xaiv autophagosome maturation [42]. Kwv yees li ntawm 10 RAB proteins muaj cov haujlwm meej hauv autophagy [43]. Yog li, RABGAPs, suav nrog TBC (TRE2-BUB2-CDC16) domain-muaj RABGAPs, kuj koom nrog hauv autophagy. RAB33B cuam tshuam rau kev tsim cov autophagosomes los ntawm kev nrhiav Atg12-Atg5-Atg16L1 complex rau hauv phagocytes, thiab Atg16L1 yog cov protein khi ntawm RAB33B [44].
Ib txoj kev tshawb fawb tau pom tias OATL1 yog GAP ua haujlwm ntawm RAB33B, thiab nws cov lus tshaj tawm tuaj yeem ncua kev loj hlob ntawm autophagosome los ntawm kev tswj cov fusion ntawm autophagosomes thiab lysosomes [45]. RalA/B (RAS zoo li A/B), ib tug tswv cuab ntawm Ras GTPase tsev neeg, kuj yog ib tug tseem ceeb regulator ntawm vesicle thauj [46]. Nyob rau hauv cov qauv ntawm cov tsiaj nyeg, RalB thiab nws cov effector protein Exo84 ua ke induce ULK1-Beclin1-VPS34 los ua ke, uas yuav tsum tau rau autophagosome tsim. Nyob rau hauv cov kev sim uas tsis muaj kev txwv tsis pub noj, qhov txo qis hauv RalGAP tuaj yeem qhib RalB thiab ua rau muaj kev nce hauv autophagy [47]. Hauv lwm qhov kev sim uas siv Drosophila ua tus qauv, cov kws tshawb fawb pom tias Ral GTPase tswj autophagy hauv cov ntsiab lus ntawm PCD [48], uas tuaj yeem suav tias yog ADCD.
Lub hom phiaj ntawm lub hom phiaj ntawm rapamycin (mTOR) integrates kev loj hlob yam tseem ceeb thiab cov khoom noj khoom haus rau inhibit autophagy. mTORC1, uas yog ib qho teeb meem nrog mTOR raws li cov khoom tseem ceeb, txhawb cov phosphorylation ntawm ULK1 (unc-51-xws li kinase 1) nyob rau hauv muaj cov as-ham txaus [49]. Raws li kev tswj hwm ntawm AKT thiab AMPK signaling kinases, tuberous sclerosis complex 1/2 (TSC1/2) ua raws li GAP ntawm Rheb (Ras homolog enriched hauv lub hlwb) los tiv thaiv kev tsim ntawm GTP-bound Rheb thiab koom nrog kev cai. ntawm Rheb-mTORC1-ULK1 taw qhia txoj hauv kev los txhawb autophagy [49–51]. Tsc1/2 deficiency yog lub luag hauj lwm rau kev loj hlob ntawm tuberous sclerosis complex (TSC), ib tug autosomal dominant teeb meem uas predisposes cov neeg mob mus rau kev loj hlob ntawm cov qog nqaij hlav ntawm ntau yam kabmob [52]. Yog li ntawd, qhov tsis zoo autophagy hauv TSC tuaj yeem ua rau muaj cov kab mob autophagic substrates, suav nrog cov protein thiab cov organelles txawv txav, hauv cov cell, txhawb cov qog nqaij hlav. Cov kev tshawb fawb kuj tau pom tias qhov kev tshem tawm ntawm RalGAP ua rau muaj kev nce hauv mTORC1 kev ua, ua rau txo qis hauv autophagy.
Lub caij no, hauv kev mob qog noj ntshav pancreatic, RalGAP suppresses qog cell invasion los ntawm mTORC1 signaling [53]. Autophagy tsub kom qhov kev tiv thaiv ntawm cov qog hlwb rau chemotherapy thiab radiotherapy. Temozolomide (TMZ) rau kev kho mob ntawm glioblastoma (GBM) yog nquag ua rau autophagy thiab tuaj yeem ua rau cov qog hlwb tiv taus cov tshuaj. DAB2IP tau pom tias tsis zoo tswj ATG9B kev qhia los ntawm Wnt / -catenin signaling txoj kev, yog li inhibiting TMZ-induced autophagy thiab nce tshuaj rhiab heev hauv GBM hlwb [54]. Tsis tas li ntawd, DAB2IP kuj tau pom tias yog tus tswj tsis zoo ntawm autophagy-txog hluav taws xob tiv thaiv hauv PCa. Raws li tus tswj hwm dej ntws ntawm DAB2IP, miR-32 downregulates protein theem ntawm DAB2IP los ntawm kev tsom nws 3'-UTR thiab inhibiting nws txhais lus [55]. Tom qab ntawd, txoj kev downstream mTOR-S6K tau qhib, tab sis kev ua haujlwm autophagy tau txhim kho, uas tuaj yeem yog qhov tshwm sim ntawm kev tawm tswv yim tsis zoo ntawm Akt [56], thaum kawg txhim kho cov hluav taws xob tiv thaiv ntawm PCa hlwb [55, 57].
Qee qhov GAPs cuam tshuam rau lub paj hlwb los ntawm kev tswj autophagy. SIPA1L2, Rap GTPase-activating protein, tswj cov txheej txheem ntawm neurotransmitter liberation, uas txuas nrog TrkB / Rap1 signaling thiab amphisomes uas yog fusion organelles ntawm TrkB-late endosomes nrog autophagosomes [58], thaum lwm tus, suav nrog TBC1D5 thiab TBC1D1. yog txuam nrog lub cev muaj zog neuron kab mob, thiab GAPs no ua rau cov txheej txheem degradable ntawm autophagy thiab sib sau ua ke ntawm cov proteins lom [59–63]. SGSM3 / RABGAP5 thiab TBC1D10A ob qho tib si tsis ua haujlwm rau GTPases sib raug zoo los txiav tawm autophagy thiab muaj kev cuam tshuam rau lub cev tsis muaj zog thaum autophagy tshem tawm cov kab mob thiab ua rau cov kab mob ntawm cov hlwb [64, 65]. Qhov tsis muaj GAPs tuaj yeem ua rau cov kab mob genetic heterogeneous autosomal kab mob. Piv txwv li, kev tshem tawm ntawm TBC1D20 cov protein tuaj yeem ua rau muaj kev sib tsoo ntawm Warburg Microsyndrome 4, uas yog ib qho mob autosomal thiab muaj qhov txawv txav ntawm qhov muag, hlwb, thiab qhov chaw mos [66]. Autophagy kuj yog ib txoj hauv kev los tswj cov metabolism thiab rov ua cov khoom noj thaum tshaib plab lossis kev ntxhov siab. TBC1D5 khi thiab sequesters LC3 ntxiv rau autophagic compartments thiab nce qabzib thauj khoom GLUT1/Slc2a1 qhia ntawm cov ntshav plasma, ua kom cov piam thaj uptake thiab glycolytic flux [67].
Hauv kev xaus, GAPs feem ntau txo qis cov kev ua haujlwm GTPase ncaj qha los tswj autophagy kom cuam tshuam rau peb lub cev ua haujlwm, tab sis ob peb tus neeg ua haujlwm tsis ncaj qha tswj autophagy kom ua tiav lub hom phiaj ntawd. Autophagy muaj feem cuam tshuam nrog lub cev homeostasis thiab kev noj qab haus huv. Qhov tseem ceeb, GAPs cuam tshuam cov txheej txheem ntawm autophagy. Hmoov tsis zoo, ADCD nws tus kheej muaj ntau qhov chaw tsis tau tshawb nrhiav, thiab vim li ntawd, muaj qee qhov kev tshawb fawb txog ADCD thiab GAPs. Peb tsuas tuaj yeem xam lub luag haujlwm ntawm GAPs hauv ADCD los ntawm kev sib txuas ntawm autophagy thiab GAPs. Yog li ntawd, cov kev tshawb fawb ntxiv yog tsim nyog los muab rau peb kom nkag siab zoo txog yuav ua li cas GAPs tswj ADCD nyob rau hauv lub cev thiab pathological xwm txheej, kom nkag siab txog kev txhim kho pathological, thiab nrhiav cov hom phiaj kho mob.
Ferroptosis
Ferroptosis yog ib qho tshiab oxidative RCD uas cov txiaj ntsig tau sau los ntawm cov hlau tuag nyob ntawm lipid hydroperoxides [68]. Nws txoj kev tshawb fawb tau pib qhov kev sim ntawm elastin-induced xaiv cell tuag nyob rau hauv 2003, thiab lo lus "ferroptosis" yog coined nyob rau hauv 2012 [69]. Tom qab ntawd, cov kws tshawb fawb tau tsim cov kev tshawb fawb ferroptosis. Qhov tshwj xeeb ntawm nws cov morphology yog mitochondrial kev hloov pauv uas suav nrog me me, hloov pauv ntawm daim nyias nyias, txo lossis ploj ntawm mitochondrial crista, thiab rupture ntawm daim nyias nyias [70]. Ferroptosis yog txuam nrog ntau yam kab mob, nrog rau mob raum raug mob, mob qog noj ntshav, thiab kab mob plawv. Ib feem ntawm qhov induction ntawm ferroptosis yog RASdependent [71]. Hauv Ras mutant qog noj ntshav, thaiv txoj hauv kev RAS-RAF-MEK inhibits ferroptosis tshwm sim los ntawm elastin, uas yog cov tshuaj tiv thaiv kab mob uas txhawb nqa kev tuag ntawm tes [72]. Txawm li cas los xij, tsis tshua paub txog kev sib txuas ntawm GAPs thiab ferroptosis.
Ntau tus lej ntawm cov cim molecular thiab txoj hauv kev tau piav qhia rau autophagy raws li cov txheej txheem ua tau ntawm ferroptosis [9, 73]. GTPases thiab GAPs uas muaj lub luag haujlwm hauv autophagy kuj tuaj yeem yog tus tswj hwm ntawm ferroptosis. RAB7A koom nrog hauv autophagy-induced degradation ntawm lipid droplets (LDs), thiab nrog lipid peroxidation exacerbates ferroptosis [74]. Raws li, TBC1D2, raws li tus tswj tsis zoo ntawm RAB7A, tuaj yeem tswj hwm ferroptosis hauv RAB7A-raws li [75]. G3BP1 (Ras-GTPase-activating protein-binding protein 1) yog koom nrog hauv kev hloov ntawm Ras signaling pathway. Cov txheej txheem ntawm nws-induced cell tuag yog txuas nrog ntev noncoding RNA P53RRA, uas yog tswj los ntawm LSH thiab p53. Thaum cov txheej txheem ntawd, nucleotides 1 thiab 871 ntawm P53RRA ncaj qha cuam tshuam nrog RNA paub txog kev sib cuam tshuam ntawm G3BP1 (aa 177-466), tsim P53RRA-G3BP1 complex. Hauv cytoplasm, P53RRA-G3BP1 kev sib cuam tshuam cuam tshuam p53 los ntawm G3BP1 complex, ua rau kev hloov pauv ntawm p53 mus rau p53 hloov pauv ntawm cytoplasm mus rau lub nucleus, uas ua rau lub p53 taw qhia txoj hauv kev thiab cuam tshuam rau kev qhia ntawm ntau yam kab mob metabolic, xws li TIGAR. thiab SLC7A11, thaum kawg ua rau lub voj voog ntawm tes raug ntes, uas ua rau apoptosis thiab ferroptosis [76].
Pyroptosis
Pyroptosis yog hom kab mob RCD uas yog lub cev tiv thaiv kab mob los tiv thaiv kab mob cuam tshuam thiab tswj lub cev homeostasis [77]. Caspase-1/4/5/11 activation yog induced los ntawm ib co inflammasomes, uas ua rau kom lub cleavage tus nqi ntawm gasdermin D thiab secrete mature inflammatory cytokines, xws li interleukin -18 thiab interleukin-1 [78 ]. Nws cov yam ntxwv yog DNA fragmentation, cell o, thiab npuas uas thaum kawg rupture plasma membrane.
Kev sib txuas ntawm pyroptosis thiab GAPs yog tshwm sim hauv kev tuag ntawm tes los ntawm qee yam kab mob. YopE yog ib hom Yersinia txheej protein (Yops) thiab tuaj yeem ua tus tswv tsev GAP ntawm Rho GTPase los ntawm hydrolyzing GTP-bound Rho GTPase nyob rau hauv ib qho kev tsis sib haum xeeb hauv Yersinia. Thaum lub sij hawm Yersinia kab mob thiab cell tuag induction, YopE muaj lwm tus neeg koom tes, YopT, cysteine protease uas covalently decomposes C-terminus ntawm Rho GTPase, yog li ua rau Rho GTPase dissociation thiab inactivation. Txawm hais tias YopE thiab YopT yog qhov tseem ceeb sib txawv ntawm Rho GTPase inactivation, ob qho tib si yog Rhomodifying co toxins uas cuam tshuam tus tswv ntawm lub cev lub cev thiab evade lub cev tiv thaiv kab mob. Cov txheej txheem no yog ncaj qha induced nyob rau hauv ib yam uas dephosphorylates lub nquag Ser205 thiab Ser241 qhov chaw ntawm pyrin thiab tsim ib tug pyrin inflammasome, thaum kawg ua rau pyroptosis [79].
Entosis cell tuag
Hauv xyoo 2007, cov kws tshawb fawb tau piav qhia txog cov txheej txheem kev tuag ntawm cov cell nonnapoptotic entosis kom suav rau qhov tshwm sim ntawm cell-noj tshwm sim pom ntawm cov qog hlwb [80, 81]. Thaum cov cell nyob tau noj los ntawm tib yam lossis ntau hom hlwb, ib qho "cell nyob rau hauv ib lub cell" qauv tshwm sim, ua rau tuag ntawm internalized hlwb (entotic cells). Tuag entotic hlwb tsis muaj morphological thiab molecular yam ntxwv ntawm apoptosis tab sis muaj autophagy dependence, nrog lysosome thiab vacuolar membrane autophagy protein-dependent fusion inducing entosis [82, 83].
Cell adhesion thiab cytoskeletal rearrangement yog cov txheej txheem tseem ceeb hauv entosis thiab tsis tuaj yeem txhais tau hauv epithelial cadherin thiab Rho-ROCK signaling [80]. Kev nrhiav neeg ua haujlwm ntawm p190A RhoGAP ntawm cell-cell junctions inhibits kev ua haujlwm ntawm Rho txoj hauv kev, ua rau txo qis hauv myosin teeb saw phosphorylation, uas txo qis actomyosin contraction thiab suppresses calmodulin qib. Vim lub polarized faib ntawm p190A RhoGAP, qhov contraction ntawm actin nyob rau hauv lub distal kawg ntawm cell adhesion yog ho siab tshaj qhov chaw ntawm cell adhesion [84]. Tsis tas li ntawd, Rho yog qhib los ntawm RhoGEF ntawm qhov kawg ntawm lub cell adhesion [85]. Yog li ntawd, RhoGAP thiab RhoGEF ua cais rau Rho tab sis synergistically rau induction ntawm ketosis.
Mitotic kev puas tsuaj
Mitotic catastrophe (MC) yog ib hom kev txawv txav ntawm mitotic cell tuag uas tseem yog ib qho kev tiv thaiv kab mob thiab kev kho mob [86]. Nws cov yam ntxwv morphological yog qhov tshwj xeeb ntawm kev hloov pauv nuclear uas feem ntau pom muaj ntau lub nucleation thiab / lossis micronucleation [87]. Kom meej meej, MC tsis yog hom RCD vim MC, zoo li autophagy, tsis tas yuav ua rau cell tuag, thiab yog li, Nomenclature Committee on Cell Death 2018 pom zoo siv lo lus mitotic tuag raws li lub npe ntawm hom kev tuag [10 ]. Ntxiv mus, cov kev tshawb fawb tau pom tias txoj hmoo kawg ntawm feem ntau MC hlwb yog intrinsic apoptosis [10, 88], nrog rau qhov sib txawv thiab kev sib txuas ntawm ob.
Tsob ntoo hom GAPs txuas nrog aberrant mitosis: RasGAP NF1, p190RhoGAP, thiab RanGAP. Kev hloov pauv hauv NF1 tuaj yeem qhib RAS cuam tshuam txog kev taw qhia hauv qab. Hauv qhov no, kev sib koom tes ntawm lwm txoj hauv kev taw qhia, xws li PKC-txog txoj hauv kev, yog xav tau los tswj cov cellular cuam tshuam ntawm RAS overactivation thiab xav tau los xyuas kom meej cell ciaj sia taus. Nyob rau hauv Nf1-cov kev mob tsis txaus, kev tawm tsam ntawm endogenous protein kinase C (PKC) feem ntau yuav koom tes nrog Akt (ib qho ntawm cov kev cuam tshuam qis qis ntawm aberrant Ras) txoj hauv kev los qhib Chk1, ncua ntev mitotic ntes thiab tom qab ua rau apoptosis ntawm MC [89]. Kev nthuav tawm ntau dhau ntawm T-cell malignancy 1 (MCT-1) cuam tshuam qhov kev nthuav qhia ntawm PTEN gene thiab cuam tshuam tsis zoo rau kev ruaj ntseg thiab kev ua haujlwm ntawm nws cov protein, ua kom phosphoinositide 3 kinase / AKT signaling. Tsis tas li ntawd, MCT{12}} downregulated p190RhoGAP thiab upregulated qhov kev qhia ntawm p190B, uas khi Src, cuam tshuam nrog MCT-1, thiab qhib Src/p190B signaling. Thaum kawg, qhov kev nthuav qhia ntau ntxiv ntawm MCT-1 thiab qhov inhibited PTEN synergistically augment Src/p190B txoj kev, uas ua rau muaj kev nyuaj siab ntawm RhoA kev ua ub no thiab txhim kho qhov tshwm sim ntawm MC [90].
Nyob rau hauv sib piv rau cov lus piav qhia ntawm cov saum toj no GAPs, ntxiv rau lub kinetochore thiab spindle localization ntawm RanGAP1 raug cuam tshuam los ntawm importin 1, uas yog ib tug regulator koom nyob rau hauv lub vector ntawm lub ntsiab interphase nuclei thiab mitotic kev loj hlob, RanGAP1 sumoylation kuj muaj feem xyuam rau importin. 1 thiab qhia txog kev sib raug zoo. Cov txheej txheem feem ntau yuav yog RanBP2 ncaj qha cuam tshuam nrog N-lub ntsiab lus ntawm importin 1, sequesters endogenous RanBP2, txo nws thiab importin 1, thiab diffuses ob qho tib si, ua rau muaj qhov txawv txav ntawm qhov sib txawv thiab qhov tsis zoo ntawm chromosome kev sib raug zoo, uas thaum kawg ua rau cell tuag [91] . Hauv cov ntsiab lus, cov kev cai txawv txav ntawm GTPase cov protein sib raug zoo los ntawm GAPs tuaj yeem cuam tshuam cov teeb liab li qub thiab thaum kawg nce tus nqi ntawm MC xwm txheej.
Cov txheej txheem
Methuosis yog ib daim ntawv tshwj xeeb ntawm RCD, thiab nws cov cim tshwj xeeb yog vacuolization, tsub zuj zuj ntawm vesicles (ib daim nyias nyias thiab los ntawm macropinosomes, qhov txawv ntawm cov qauv ntawm ob daim nyias nyias ntawm autophagosomes), thiab thaum kawg plasma membrane rupture [92]. Methuosis zoo sib xws nrog Ras signaling pathway (kev ua kom tsis tu ncua), uas yog tus cwj pwm los ntawm GBM thiab gastric carcinoma [93].
GIT1 ua haujlwm raws li GAP rau inactivate Arf6 los ntawm hydrolyzing GTP los cuam tshuam txoj kev. Hauv cov txheej txheem ntawd, hyperactive H-Ras qhib lub Rac1 GEF, nce tus nqi ntawm Rac1-GTP. Micropinocytosis txhim kho los ntawm kev ua kom Rac1 thiab clathrin-independent endocytosis (CIE) tau txais qee yam ntawm cov endosomes lig (Rab7 thiab LAMP1). Lub caij no, muaj cov tswv yim tawm tswv yim uas ua rau lub siab ua haujlwm Rac1 ua rau Rac1-GTP cuam tshuam ncaj qha nrog GIT1, txo qis kev ua haujlwm ntawm Arf6, cuam tshuam kev rov ua dua ntawm CIEs, thiab tsis ua haujlwm nrog lysosomes. Thaum kawg, cov kev tshwm sim no ua rau cov tsub zuj zuj ntawm CIE, thiab lig endosomal vesicles sib koom ua ke, yog li tsim cov kua dej loj dua cytoplasmic vacuoles, uas thaum kawg rupture plasma membrane thiab ua rau cell tuag [94, 95]. Txawm li cas los xij, cov txiaj ntsig saum toj no cuam tshuam Shliom thiab cov npoj yaig cov nyiaj txiag uas Arf6 (Q67 L) kev ua haujlwm txhawb kev tsim cov vacuole hauv cov hlwb uas qhia H-Ras (G12V) [96]. Qhov kev piav qhia tsim nyog tshaj plaws rau qhov tshwm sim no yog tias lawv cuam tshuam cov vacuoles uas tshwm sim
GAPs tswj cov qog tiv thaiv kab mob
RCD thiab kev tiv thaiv kab mob muaj feem cuam tshuam zoo
RCD tau pib xav tias yog ib qho kev tiv thaiv kab mob-tolerogenic, tshwj xeeb tshaj yog apoptosis [97]. Txawm li cas los xij, cov pov thawj tom qab thiab kev taw qhia ntawm lub tswv yim ntawm immunogenic cell tuag (ICD) tau maj mam tsim lub luag haujlwm ntawm kev tiv thaiv kab mob hauv RCD. ICD tsis yog hom kev tuag ntawm kev ywj pheej, thiab nws hais txog ib hom RCD uas muaj qhov muaj kev tiv thaiv kev tiv thaiv uas tau tsav los ntawm kev ua kom muaj cytotoxic T lymphocytes (CTLs) los teb rau kev ntxhov siab vim kev tuag ntawm tes [97, 98]. Txoj kev loj hlob ntawm ICD yog cov txheej txheem nyuaj uas muaj cov antigens tsis tau them los ntawm lub hauv paus kam rau ua nyob rau hauv cov hlwb tuag thiab raug thiab tso tawm ntawm kev puas tsuaj cuam tshuam nrog cov qauv molecular (DAMPs) yog cov khoom tseem ceeb, hu ua antigenicity thiab adjuvanticity, feem [98] ]. DAMPs txhawb kev nrhiav neeg ua haujlwm thiab kev loj hlob ntawm cov kab mob antigen-tam sim no (APCs), ua rau CTL-nyob ntawm lub cev tiv thaiv kab mob [99]. Qee cov tshuaj siv tshuaj khomob, cov kab mob oncolytic, cov tshuaj tiv thaiv kabmob kheesxaws, cov qauv siv hluav taws xob tshwj xeeb, thiab lwm yam tuaj yeem ua rau ICD [100, 101].
Raws li qhov kev tshawb pom no, xyoo 2013, cov kws tshawb fawb tau qhia tias kev sib txuas ntawm ICD inducers nrog rau lwm cov immunomodulators tuaj yeem ua rau muaj txiaj ntsig zoo rau cov tshuaj tiv thaiv kab mob [99], thiab cov kev tshawb fawb tom qab tau lees paub tias cov tshuaj tiv thaiv kab mob monoclonal tsom rau cov tshuaj tiv thaiv kab mob tiv thaiv kab mob, xws li cytotoxic T-lymphocyte-cuam tshuam. antigen 4 (CTLA-4), programmed cell death-1 (PD-1) thiab nws cov ligand PD-L1, yog cov koom tes zoo rau ICD [102–104]. Tsis ntev los no, kev kho mob qog noj ntshav ua ke nrog nanotechnology los txhawb ICD kuj tau pom cov kev cia siab tshiab [105, 106]. Tau kawg, lwm RCDs tsis yog qhov kawg ntawm lub xovtooj tab sis tuaj yeem yog qhov pib ntawm kev tiv thaiv kab mob lossis txawm tias ICD [107]. Ntxiv mus, cov RCDs no tseem koom nrog kev tiv thaiv kab mob [108, 109]. Piv txwv li, T hlwb thiab ferroptosis kho ib leeg hauv cov qog. Immunotherapy-activated CD8 ntxiv rau T hlwb txhim kho lipid peroxidation nyob rau hauv cov qog hlwb, uas nyob rau hauv lem ua rau lub antitumor efficiency ntawm immunotherapy nrog nce ferroptosis [110]. Cov ntaub ntawv pov thawj no txaus los ua pov thawj tias RCD yog inextricably txuas rau kev tiv thaiv kab mob thiab kev tiv thaiv kab mob.
GAPs pab txhawb kev tiv thaiv kab mob microenvironment
Kev tsim thiab basal muaj nuj nqi ntawm ntau lub cev tiv thaiv kab mob yog cuam tshuam los ntawm GAPs (Fig. 4A). T hlwb yog lub hauv paus ntawm kev tiv thaiv kab mob. Tsis paub qab hau ob qhov zoo (DP) thymocytes yog ib feem sib txawv rau hauv CD4 ntxiv lossis CD8 ntxiv rau ib leeg-zoo (SP) T hlwb tom qab xaiv qhov zoo, thaum lwm cov DP T hlwb raug apoptosis. Lub tshuab uas Ras-MAPK txoj hauv kev tswj cov txheej txheem no tau kawm zoo [111, 112].
Hauv RASA1- tsis muaj thymus, DP hlwb tau nce qhov kev pheej hmoo ntawm apoptosis, tab sis qhov nce CD4 SP rau DP piv qhia tias RASA1 tshem tawm txhawb kev xaiv zoo thiab tuaj yeem cuam tshuam nrog Ras-MAPK qhia txoj hauv kev ua kom [113]. Tsis tas li ntawd, muab cov nyhuv proapoptotic ntawm DAB2IP, CCR4-TSIS complex downregulates DAB2IP los koom rau hauv kev xaiv zoo ntawm thymocytes [114]. Interestingly, lwm txoj kev tshawb fawb pom tias NF1 txhawb kev xaiv zoo ntawm thymocytes hauv poj niam HY TCR Tg nas, tab sis cov txheej txheem tsis meej [115]. Lwm qhov piv txwv ntawm T cell regulation yog ARHGAP19 tswj cov cytoskeletal remodeling xav tau rau T lymphocyte division thiab tswj chromosome segregation los ntawm regulating RhoA [116]. ARHGAP45 tuaj yeem tswj hwm RHO los tswj kev hloov pauv hauv cytoskeleton ntawm cov hlwb tsis paub T hlwb, nce lawv cov deformation thiab tsiv mus rau cov qog nqaij hlav (LNs), thiab txhawb nqa thymic noob ntawm T cell progenitors [117].
Tsis tas li ntawd, Rab35 thiab nws cov GAP EPI64C (TBC1D10C) yuav tsum muaj nyob rau hauv kev tsim ntawm immunological synapses (ISs), uas yog ib feem ntawm T cell-APC kev sib cuam tshuam [118]. Macrophages ua lub luag haujlwm tseem ceeb hauv qab ntawm lub cev tiv thaiv kab mob los ntawm kev cuam tshuam cov hlwb tuag. Cov kev tshawb fawb yav dhau los tau pom cov tswvcuab Rho GTPase Rac1 thiab Cdc42 ua cov hloov pauv molecular uas tswj cov ntaub so ntswg cytoskeleton los tswj Fc receptor-mediated phagocytosis [119, 120]. Sh3BP1, ArhGAP12, thiab ArhGAP25 koom tes inactivated Rac thiab Cdc42 nyob rau hauv lub sij hawm thiab qhov chaw, yog li xaus lub phagocytosis ntawm macrophages rau loj hais xws li apoptotic hlwb [121]. Macrophage polarization, motility, thiab kev sib kis ntawm tes muaj feem xyuam nrog RASA{17}}kev tswj hwm kev sib kho ntawm p190RhoGAP translocation [122]. Lwm RhoGAP myosin Myo9b deletion hauv macrophages tau pom tias ua rau hloov pauv cell morphology thiab impaired migratory peev [123]. Lub luag haujlwm ntawm RhoGAP tsev neeg hauv neutrophils yog qhov dav dua, feem ntau cuam tshuam nrog kev hloov pauv ntawm neutrophil, adhesion, chemotaxis, thiab phagocytosis, raws li kev tshuaj xyuas los ntawm Roland Csépányi-Kömi li al. [124].
Nrog rau kev koom tes ntawm cov qog microenvironment, cov qog hlwb tuaj yeem khiav tawm ntawm kev soj ntsuam ntawm lub cev tiv thaiv kab mob thiab yog li ciaj sia tiv thaiv kab mob thaum lub sij hawm txoj kev loj hlob. NF1, encoding neurofibromin, yog ib qho piv txwv zoo los qhia txog lub luag haujlwm ntawm GAPs hauv cov qog tiv thaiv kab mob microenvironment (Fig. 4B). Neurofibromin yog GTPase-activating protein uas txo qis RAS kev ua haujlwm, thiab yog li, kev hloov pauv hauv NF1 tuaj yeem qhib RAS-txog kev taw qhia hauv qab. Neurofibromatosis type 1 (NF1) yog ib yam kab mob ntawm lub paj hlwb uas tshwm sim los ntawm kev poob ntawm kev ua haujlwm ntawm neurofibromin protein GAPs [125]. Lub cev tiv thaiv kab mob xws li infiltrating inflammatory mast cells yog ib feem ntawm NF1, thiab kev hloov pauv ntawm NF1 noob hauv lub cev tiv thaiv kab mob kuj tseem ceeb rau tus kab mob no [126]. Cov kws tshawb fawb tsim NF1fox/−; Krox20- Cre nas nrog NF1−/− Schwann hlwb thiab NF1 ntxiv /- mast hlwb thiab pom tias nas nrog Schwann cell proliferation, nrog rau loj mast cell infiltration, tsim plexiform neurofibromas piv rau cov nas. Qhov kev tshawb pom no qhia qhov tseeb tias haploinsufficiency ntawm NF1 mast hlwb tsim NF1 ntxiv /- tiv thaiv kab mob microenvironment uas nyiam cov qog [127].
Tsis tas li ntawd, NF1−/− Schwann hlwb txhim kho Nf1 haploinsufficiency mast cell migration los ntawm qia cell factor (SCF) thiab degranulation los ntawm c-kit-mediated activation ntawm PIK-3 pathway [128–130]. Piv nrog rau cov tib neeg ib txwm muaj, cov neeg mob NF1 nquag tsim cov qog ntawm lub hauv nruab nrab paj hlwb. Hauv qib qis glioma (LGG), cov kws tshawb fawb tau tshawb pom qhov tseem ceeb ntawm cov neuroimmune axis, uas qhia tias NF1 mutant neurons tsim midkine los ntxias T hlwb kom qhib microglia los tsim CCL5, qhov tseem ceeb uas txhawb kev loj hlob ntawm LGG [131]. Cov txiaj ntsig zoo sib xws tau pom hauv GBM.
Ib txoj kev tshawb fawb tsis ntev los no tau pom tias cov qauv qog nrog codeletion ntawm Nf1 thiab Pten thiab overexpression ntawm EGFRVIII tuaj yeem khiav tawm ntawm lub cev tiv thaiv kab mob thiab qib siab ntawm kev tiv thaiv kab mob microenvironment, thiab Nf1 poob yog qhov xwm txheej tseem ceeb [132]. Interestingly, txawm hais tias qhov kev hloov pauv tsis tiav ntawm NF1 alleles yog tus tsav ntawm cov qog, qee cov kws tshawb fawb nthuav tawm qhov tsis sib haum xeeb tias qhov tsis muaj NF1 hauv T hlwb tuaj yeem ua rau T cell ua haujlwm los txhim kho lub cev tiv thaiv kab mob ntawm cov qog thiab inhibit malignant migration. Raws li qhov kev tshawb pom no, qhov tshwm sim ntawm kev kho mob ntawm NF1 cov neeg mob uas feem ntau cov qog txuam nrog NF1 yog qhov tsis zoo ntawm peb qhov kev lees paub ntawm NF1 noob kev hloov pauv [133].
Tsis tas li ntawd, cov kev tshawb fawb tau pom tias Ras protein activator-zoo li 1 protein (Rasal1) tsis zoo tswj P21Ras-ERK txoj hauv kev hauv T hlwb, yog li inhibiting kev ua haujlwm ntawm T hlwb kom txo tau cov tshuaj tiv thaiv kab mob ntawm T hlwb, thaum RASAL1 knockdown tau pom. txhawm rau txhim kho cov haujlwm antitumor ntawm T hlwb hauv B16 melanoma thiab EL-4 lymphoma [134]. Raws li GAP ntawm G proteins, RGS tsev neeg tau koom nrog hauv kev tswj hwm kev tiv thaiv kab mob hauv ntau txoj hauv kev thiab muaj peev xwm rau kev tiv thaiv kab mob [135]. Cov kev tshawb fawb tsis ntev los no tau pom tias RGS1 inhibits kev thauj mus los ntawm T1 hlwb thiab CTLs rau cov qog nqaij hlav, ua kom yooj yim tsim 'mob qog' hauv qog noj ntshav thiab ua rau muaj kev tiv thaiv kab mob tiv thaiv kab mob [136]. Lub caij no, cov kev sim nas pom tau hais tias kev hloov pauv ntawm cov qog nqaij hlav tshwj xeeb CTLs nrog RGS1 knockdown ua ke nrog PD-L1 tuaj yeem yog qhov kev cog lus tiv thaiv kab mob rau mob qog noj ntshav [136].
Cov lus xaus thiab kev pom
Kev tshawb fawb txog GAPs hauv cov kab mob, tshwj xeeb tshaj yog mob qog noj ntshav, tau nce ntxiv hauv xyoo tas los no. Qee qhov GAPs tuaj yeem yog qhov tseem ceeb hauv kev loj hlob ntawm cov qog nqaij hlav cancer, kev tsiv teb tsaws, tshuaj tiv thaiv, thiab kev hloov pauv tsis zoo thiab tuaj yeem yog cov hom phiaj kho mob tshiab thiab cov cim qhia txog kev mob qog noj ntshav. Cov kev taw qhia txoj kev cuam tshuam nrog RCD tuaj yeem hloov kho los ntawm GAPs thaum lub sijhawm ua haujlwm no. Qhov piv txwv zoo tshaj plaws yog qhov inhibition ntawm RAS-txog txoj hauv kev los ntawm RASGAPs los tswj cov txheej txheem apoptotic hauv cov qog nqaij hlav cancer. Kev tshawb fawb txog kev tswj cov qog tiv thaiv kab mob los ntawm GAPs raug txwv. Ntawm no, los ntawm kev qhia txog lub luag haujlwm dav dav ntawm GAPs hauv kev tswj hwm RCD, peb xav tias nws tuaj yeem ua tau tias GAPs muaj nyob rau hauv RCD-txog kev tiv thaiv kab mob lossis, ntau qhov tseeb, hauv ICD-induced antitumor immune teb. Tsis tas li ntawd, GAPs qhia nyob rau hauv lub cev tiv thaiv kab mob yog qhov tseem ceeb hauv kev tswj hwm lub cev kev ua haujlwm ntawm lub cev tiv thaiv kab mob thiab koom nrog hauv kev tiv thaiv kab mob thiab kev tiv thaiv kab mob los ntawm kev tswj hwm lub cev tiv thaiv kab mob.
Ib qho ntawm kev ua kom pom tseeb ntawm oncogenic RAS cov proteins yog lub peev xwm los tiv thaiv apoptosis ntawm cov qog nqaij hlav cancer kom tau txais kev loj hlob tsis muaj kev txwv. Oncogenic RAS tuaj yeem muaj kev hloov pauv uas tiv thaiv hydrolytic inhibition tshwm sim los ntawm RASGAPs.
Txawm hais tias kev tshawb nrhiav cov tshuaj molecule me me uas tuaj yeem ua tau zoo sib xws rau GAPs los txhawb RAS-GTP hydrolysis tau ntev tau thov, tsis muaj kev vam meej tau ua tiav. Nws tau raug pom tias semaphorin 4D ua haujlwm ntawm GAP-active receptor Plexin-B1 kom inactivate R-Ras thiab yog li tswj kev sib xyaw ua ke thiab kev txav ntawm tes [137]. Muaj cov piv txwv ntxiv rau kev tswj hwm cov haujlwm tshwj xeeb GAP. Piv txwv li, cov hluavtaws protein repulsive kev taw qhia molecule A (RGMA) receptor neogenin upregulates p120GAP kev ua, ua rau inhibition ntawm Ras thiab nws downstream effector Akt [138]. Inhibition ntawm kev ua haujlwm ntawm RASGAPs kuj tseem muaj nyob hauv kev mob qog noj ntshav. Txawm li cas los xij, cov kev kho mob rau cov kab mob NF1 feem ntau tseem nyuaj heev, thiab cov tswv yim tam sim no feem ntau cuam tshuam nrog kev cuam tshuam ntawm RAS / MEK txoj kev [139]. Hauv cov ntsiab lus, txawm hais tias qhov kev ua haujlwm tseem ceeb ntawm GAPs tau nkag siab zoo, cov kev tshawb fawb ntxiv yog tsim nyog kom nkag siab zoo dua li cas GAPs tswj cov txheej txheem lom neeg, kom nkag siab zoo txog kev txhim kho pathological, thiab txheeb xyuas cov hom phiaj kho mob.
Cov ntawv luv
GAP: GTPase-activating protein; RCD: tswj cell tuag; GEFs: Guanine nucleotide pauv yam; GDIs: Guanine nucleotide dissociation inhibitors; RGSs: Regulators ntawm G protein signaling; GPCR: G-protein coupled receptor; ACD: Kev tuag ntawm tes tuag; PCD: Programmed cell tuag; DISC: Tuag-inducing signaling complex; TNF: qog necrosis yam; TRAIL: TNFrelated apoptosis-inducing ligand; RGS3: Regulator ntawm G-protein signaling 3; DLC1: Tshem tawm hauv daim siab mob cancer 1; DAB2IP: DOC-2/DAB2 interacting protein; PITX1: Phosphorylation ntawm pituitary homeobox 1; HCC: mob qog nqaij hlav hepatocellular; ceRNA: Sib tw endogenous RNA; PCa: mob qog noj ntshav prostate; ECT2: Epithelial cell transforming sequence 2; YAP: Muaj cov protein sib txuas; TPR: Translocated txhawb nqa cheeb tsam; BLBC: basal zoo li mob qog noj ntshav; LV: Lymphatic hlab ntsha; ADCD: Autophagy-dependent cell tuag; mTOR: Mechanistic phiaj ntawm rapamycin; TMZ: Temozolomide; GBM: Glioblastoma; G3BP1: Ras-GTPaseactivating protein-binding protein 1; Yops: Yersinia Outer proteins; MC: Mitotic kev puas tsuaj; MCT-1: Ntau daim ntawv luam hauv T-cell malignancy 1; ICD: Immunogenic cell tuag; CTLs: Cytotoxic T lymphocytes; DAMPs: Kev puas tsuaj cuam tshuam nrog cov qauv molecular; APCs: Antigen-tshem cov hlwb; DP: Ob chav zoo; NF1: Neurofbromatosis hom 1; SCF: Stem cell factor; LGG: Qib qis glioma; Rasal1: Ras protein activator zoo li 1 protein.
Kev lees paub
Peb ua tsaug rau Prof. Yongguang Tao thiab Dr. Li Xie, thiab Wenbing Liu rau kev txheeb xyuas cov duab thiab cov ntawv sau.
Cov neeg sau ntawv pab txhawb
YJ thiab LC tau pab txhawb rau kev xav thiab tsim kev tshuaj xyuas. HH thiab SW sau ntawv. JH thiab HH npaj cov duab thiab rooj. SJ, LL, thiab YL tau sau cov ntaub ntawv pov thawj thiab koom nrog kev sib tham. Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv sau kawg
Nyiaj txiag
Txoj haujlwm no tau txhawb nqa los ntawm National Natural Science Foundation ntawm Tuam Tshoj (81802785 [YJ], 82100490 [LC]), Hunan Provincial Natural Science Foundation ntawm Tuam Tshoj (2020JJ5382 [YJ], 2020JJ5381 [LC]), Kev Tshawb Fawb Txog Kev Tshawb Fawb ntawm Hunan Provincial Health Commission (20200763 [WL]) thiab Basic Research Project ntawm Changsha Science thiab Technology Bureau (kq2004127 [LX]).
Muaj cov ntaub ntawv thiab cov ntaub ntawv
Tsis siv tau.
Cov lus tshaj tawm
Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom
Tsis siv tau.
Tso cai rau kev tshaj tawm
Tsis siv tau.
Kev nyiam sib tw
Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev nyiam sib tw.
Sau Paub meej
1 Lub Tuam Txhab Tseem Ceeb ntawm Cov Qauv Tsiaj thiab Qej Cell Biology hauv Hunan Xeev, Hunan Normal University, Changsha 410013, Hunan, Tib Neeg Lub Tebchaws ntawm Tuam Tshoj. 2 Lub Tsev Kawm Ntawv Tshuaj, Hunan Normal University, Changsha 410013, Hunan, Tib neeg lub koom pheej ntawm Tuam Tshoj. 3 Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China. 4 Lub Chaw Haujlwm Tseem Ceeb ntawm Carcinogenesis thiab Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha 410078, Hunan, People's Republic of China.
Cov ntaub ntawv
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