Me Rab GTPases hauv Intracellular Vesicle Trafficking: Case Ntawm Rab3A/Raphillin-3Ib qho nyuaj hauv lub raum
Mar 30, 2022
Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791
Abstract:Me Rab GTPases, pawg loj tshaj plaws ntawm cov me me monomeric GTPases, tswj vesicle traf-finicking hauv hlwb, uas yog ib qho tseem ceeb rau ntau cov txheej txheem ntawm tes. Lawv lub luag haujlwm hauv cov kab mob neurological, xws li mob qog noj ntshav thiab o tau raug tshawb fawb ntau, tab sis lawv qhov cuam tshuam hauv cov kab mob raum tsis tau tshawb fawb tob. Rab3a thiab nws cov effector Rabphillin-3A (Rph3A) qhia tau pom tias muaj nyob rau hauv podocytes ntawmib txwmlub raumntawm nas nas thiab tib neeg, nyob ib ncig ntawm vesicles uas muaj nyob rau hauv cov txheej txheem ntawm ko taw, thiab lawv overexpressed nyob rau hauv cov kab mob nrog proteinuria. Tsis tas li ntawd, Rab3A knockout nas qauv ua rau muaj kev hloov pauv cytoskeletal hauv podocytes ntawm cov tsiaj noj qabzib siab. Ib yam li ntawd, RphA cuam tshuam hauv tus qauv Drosophila ua rau cov qauv thiab kev ua haujlwm puas tsuaj hauv nephrocytes nrog txo qis infiltration capacities thiab nephrocyte tooj. Kev hloov pauv hauv cov qauv ntawm lub plawv fiber ntau hauv tib tus qauv RphA cuam tshuam, qhib cov lus nug yog tias Rab3A ua haujlwm tsis zoo yuav tsim kev puas tsuaj rau lub plawv thiablub raum hlwb,ib qho chaw txaus nyiam uas yuav xav tau kev saib xyuas yav tom ntej.
Ntsiab lus:Rab proteins; Rab 3A; Rabphilin-3A, lub cev, lub cev
Taw qhiaMe Rab GTPases, pawg loj tshaj plaws ntawm me me monomeric GTPases, thiab lawv cov Rabinteracting proteins koom nrog ntau lub cellular zog nrog rau kev khiav ntawm endosomal vesicles thiab plasma membrane ua ke kom tso cov khoom thauj mus rau qhov chaw extracellular [1,2]. Lub luag haujlwm ntawm Rab GTPases hauv cov kab mob thiab cov tsos mob tshwj xeeb tau raug tshawb xyuas dav [3]. Kev soj ntsuam loj thiab cuam tshuam hauv vesicle synapses thiab tso nyiaj hauv cov kab mob hauv lub paj hlwb, cov pov thawj ntawm lawv txoj kev koom tes hauv lwm cov ntaub so ntswg thiab cov txheej txheem pathological xws li mob qog noj ntshav, o, platelet, thiab endocrine secretions yog qhov kev xav ntawm kev tshawb fawb hauv xyoo tas los no. Ua haujlwm tau zoo, Rab GTPases koom tes nrog cov khoom lag luam membrane raws li kev hloov pauv hloov pauv ntawm cov xeev nquag GTP thiab cov xeev tsis ua haujlwm hauv GDP. Daim ntawv GTP-txheej txheem tuaj yeem cuam tshuam nrog cov nyhuv, txhawb ntau cov kauj ruam thiab pab txhawb rau vectorial membrane tsheb [2]. Txhua Rab protein muaj cov proteins tshwj xeeb uas tswj cov txheej txheem thauj mus los hauv lub cev sib txawv, uas yog cov trans-Golgi network, endosomal pathway-lysosome rau clearance / degradation, los yog fusion nrog cellular membrane rau vesicle tso tawm yog feem ntau kawm [4-6].
Rabs cuam tshuam nrog caj ces thiab kis kab mob [7]. Lawv cuam tshuam rau mob qog noj ntshav,kab mob neurologic, tiv thaiv kab mob,thiab kab mob tau lees paub [8]. Txawm hais tias muaj kev paub ntau ntxiv, lawv qhov kev pab cuam rau lub raum thiab lub plawv tsis ua haujlwm thiab kev puas tsuaj yog tsawg. Yog li, qhov kev tshuaj xyuas no muab cov ntsiab lus ntawm qhov cuam tshuam ntawm Rab GTPases hauv tib neeg cov kab mob, nrog rau kev tsom tshwj xeeb rau Rab3a-Rph3A complex thiab nws lub luag haujlwm tseem ceeb hauv cov kab mob raum thiab hais txog kev cuam tshuam yav tom ntej.
Rab GTPases thiab Vesicle TraffickingRab proteins [9] yog tus thawj tswj hwm ntawm kev thauj mus los ntawm lub cev ntawm lub cev ntawm cov khoom sib txawv los ntawm kev nrhiav neeg ua haujlwm thiab cov neeg tswj xyuas tshwj xeeb [2], koom nrog hauv cov vesicle budding, kev txav mus los ntawm kev cuam tshuam nrog cytoskeleton, lossis tethering rau daim nyias nyias. Tsev neeg Rab yog tsim los ntawm ntau dua 70 GTPases, txhua qhov yog qhov tshwj xeeb tshaj plaws nrog rau ib qho kev sib txuas hauv lub cev kom tswj tau qhov tshwj xeeb thiab kev taw qhia ntawm txoj kev lag luam membrane, feem ntau cuam tshuam nrog kev thauj mus los ntawm vesicular. Hauv kev ua li ntawd, lawv pab txhawb rau kev sib tham txog daim nyias nyias nyias [10] thiab xyuas kom meej tias cov khoom thauj membrane raug thauj mus rau lawv qhov chaw nyob hauv lub cell.
Cov txheej txheem muaj cov txheej txheem kev lag luam zoo, suav nrog txoj hauv kev exocytic thiab endocytic, nrog rau tom kawg suav nrog cov khoom siv thaum ntxov, lig, thiab rov ua dua tshiab [11]. Txhua txoj hauv kev yog feem ntau embedded nrog tsis-overlapping Rabs thiab tshwm sim nyob rau hauv sib txawv compartments (Daim duab 1).
Koom nrog trans-Golgi network thiab secretory vesicles, ob peb Rab proteins tau txheeb xyuas. Rab1 pab txhawb lub budding ntawm vesicles ntawm lub endoplasmic reticulum tawm qhov chaw thiab translocation ntawm vesicles mus rau lub pre-Golgi intermediate compartment [12]. Kev hloov pauv ntawm cov hlwv los ntawm endoplasmic reticulum mus rau pre-Golgi kuj tseem yuav raug tswj los ntawm Rab2- tus neeg sib haum xeeb rov qab. Rab8 relays vesicle trafficking nyob rau hauv txoj kev secretory coj los ntawm trans-Golgi network mus rau plasma membrane. Rab3 subfamily cov tswv cuab yog cov tswj hwm tseem ceeb ntawm secretory vesicle exocytosis hauv eukaryotic hlwb, tab sis kev tshawb fawb tsis ntev los no qhia tau hais tias ntxiv Rab isoforms, Rab27 subfamily, yuav tsum muaj rau cov txheej txheem no [13]. Cov ntaub ntawv tsis ntev los no tau tshaj tawm tias Rab3 thiab Rab27 koom tes ua kom tiav vesicle exocytosis los ntawm kev nrhiav cov proteins tshwj xeeb, xws li Rabphilin3a (Rph3a) uas khi Rab27a, recruiting ib qho activating enzyme Rab3IL1, Rab regulator, uas catalyzes pauv ntawm GDP rau [GTP1 ntawm Rab3. ]. Rph3a tsav vesicle docking ntawm lub hom phiaj membranes. Txawm li cas los xij, qee qhov secretory vesicles. Rph3a tsav vesicle docking ntawm lub hom phiaj membranes. Txawm li cas los xij, qee qhov secretory vesicles tej zaum kuj yog tsim los ntawm kev ncaj qha budding ntawm plasma membrane, thiab qhov yuav tsum tau rau Rab GTPase kev ua si nyob rau hauv xws li secretion tsis paub.
Daim duab 1. Rab proteins-mediated intracellular vesicular thauj. Highlighted Rab tsev neeg cov proteins uas ua lub luag haujlwm tseem ceeb hauv kev tswj cov cellular membrane kev lag luam suav nrog endocytosis, exocytosis, exosome secretion, thiab vesicles xa ntawm organelles. Me Rab GTPases ua lub luag haujlwm tseem ceeb hauv kev tswj hwm cellular vesicular kev lag luam suav nrog endocytosis, exocytosis, exosome secretion, thiab intracellular vesicles xa. Rab5, uas yog nyob rau hauv thaum ntxov endosomes mediates endocytosis thiab endosome fusion ntawm vesicles. Rab11 thiab Rab25 kho qhov kev rov ua kom rov qab qeeb qeeb los ntawm kev rov ua dua endosomes, thaum Rab4 mediates ceev endocytic recycling ncaj qha los ntawm cov endosomes thaum ntxov. Lub lig endosome-lysosome kev sib txuas nrog Rab7 kho qhov kev loj hlob ntawm lig endosomes thiab lawv fusion nrog lysosomes. Lwm qhov lig endosomal GTPase, Rab9, kho kev lag luam los ntawm lig endosomes mus rau trans-Golgi network (TGN). Rab1, nyob ntawm qhov chaw tawm ntawm endoplasmic reticulum (ER) thiab lub pre-Golgi intermediate compartment (IC), kho ER-Golgi kev lag luam. Rab2, nyob ntawm IC, kuj tseem tuaj yeem tswj hwm Golgi-ER kev lag luam. Rab6 feem ntau yog lub npe hu rau intra-Golgi kev lag luam ntawm vesicles. Rab8 kho kom haum rau kev lag luam los ntawm TGN mus rau plasma membrane, thaum Rab3 thiab Rab27 kho ntau hom kev tswj hwm exocytic. Rab22 mediates kev lag luam ntawm TGN thiab thaum ntxov endosomes thiab vice versa. Thaum kawg, rau lub cev multivesicular (MVB)-dependent secretion, Rab11, Rab35, thiab Rab27, tau pom los txhawb exosome secretion thiab tej zaum yuav ua rau sib txawv MVBs raws txoj kev endocytic. MVB: ntau lub cev; TGN: trans-Golgi network.
Nyob rau hauv kev sib raug zoo rau endocytosis thiab recycling endosome txoj kev, Rab5 yog ib tug neeg nyob rau hauv thaum ntxov endosomes, phagosomes, plasma daim nyias nyias, thiab mediates endocytosis nrog clathrin-coated vesicles. Rab11 thiab Rab25 koom nrog hauv kev rov ua dua tshiab endosome thiab Rab4 pab txhawb kev rov ua dua tshiab ntawm endosomes los ntawm cov neeg endosome thaum ntxov. Tom qab ntawd, Rab7 kho qhov kev loj hlob ntawm lig endosome (LE) thiab tom qab ntawd coj LE mus rau lysosome rau degradation. Thaum kawg, Rab9 txuas LE mus rau trans-Golgi network. Tsom ntsoov rau exosome secretion, muaj cov tshiab molecular players nyob rau hauv pathogenesis ntawm ntau yam kab mob, Rab11 yog thawj tshaj qhia [15]. Tom qab ntawd, ob lub Rabs tshiab tau hais meej hauv exosome secretion, Rab27 thiab Rab35, ob qho tib si tso cai rau docking ntawm multivesicular lub cev (MVBs) mus rau plasma membrane. Silencing thwmsim ntawm Rab2B, Rab5A, Rab9A, Rab11, thiab feem ntau ua tau zoo Rab27A thiab Rab27B txo qis qis ntawm exosomes [16–18]. Txawm li cas los xij, cov kev soj ntsuam ntawm tus kheej no txawv raws li hom cell txheeb xyuas thiab cuam tshuam los ntawm kev sib txawv ntawm exosome enriched nrog cov khoom sib txawv. Rab11 thiab Rab35 feem ntau cuam tshuam nrog kev rov ua dua tshiab thiab kev txheeb xyuas ntxov endosomes, feem, thiab Rab27A / B mus rau lig endosomal thiab secretory compartments, feem ntau hu ua lysosome-related organelles [9]. Yog li, sib txawv subtypes ntawm lig endosomes tuaj yeem tsim cov exosomes sib txawv [19]. Tej zaum exosome ntau haiv neeg nyob rau hauv cov protein cargoes tuaj yeem yog vim muaj kev sib txawv ntawm kev sib txawv ntawm kev khiav tsheb khiav los ntawm Rab proteins tshwj xeeb raws li kev txhawb nqa ntawm tes.
Ntxiv mus, Rab kev sib cuam tshuam nrog cov nyhuv tswj vesicle targeting thiab membrane fusion nyob rau hauv peb txoj kev [20]. Ua ntej, Rabs pab nyob rau hauv lub carriage ntawm vesicles los ntawm lawv qhov chaw ntawm lub hauv paus chiv keeb mus rau lub receiver compartments los ntawm cytoskeleton ntsiab thiab lub cev muaj zog proteins. Qhov thib ob, Rab effectors tswj cov khoom lag luam ntawm cov vesicle docking kauj ruam. Thib peb, nyob rau hauv daim nyias nyias fusion ntawm vesicles yog SNAREs-tsav docking ntawm daim nyias nyias [20]. Hauv cov ntsiab lus, qhov tshwj xeeb hauv cheeb tsam sib txawv ntawm Rab GTPases rau cov txheej txheem membrane thiab lawv lub peev xwm los tswj cov kev lag luam tshwj xeeb, tau ua rau lawv txaus nyiam raws li cov hom phiaj tshiab molecular. Txawm li cas los xij, muaj ib feem kev paub txog kev ua haujlwm meej thiab qhov cuam tshuam ntawm tshaj-lossis qis-qhia ntawm Rab GTPases ntawm vesicle tsheb tau txais los ntawm heterogeneity ntawm kev ua haujlwm nyob rau hauv ntau hom cell nrog nyuaj los txheeb xyuas lawv cov kinetics. Kev loj hlob ntawm cov thev naus laus zis tshiab, xws li kev daws teeb meem siab confocal microscopy [21] thiab CRISPR / Cas thev naus laus zis, pab txhawb kom tau txais cov ntaub ntawv tseem ceeb thiab kev nkag siab ntau dua ntawm lub luag haujlwm ntawm Rab GTPases hauv vesicle biogenesis thiab secretion, nthuav tawm yav dhau los tsis paub txog lub cev lub cev thiab yog li nws cuam tshuam rau kev noj qab haus huv thiab kab mob.
cistanche muag
Rab-Mediated Vesicular Traffic thiab Kab MobKev tswj xyuas meej ntawm cov txheej txheem kev lag luam membrane los ntawm Rab GTPases yog nyob ntawm kev cuam tshuam nrog cov nyhuv, tswj cov polarity ntawm cov hlwb kom ua tiav qhov ua tau zoo tshaj plaws ntawm kev ua haujlwm thiab cov qauv, thiab tswj cov xov tooj ntawm tes, kev faib tawm, kev ciaj sia, thiab kev tsiv teb tsaws [22,23]. Yog li, lawv qhov tseem ceeb hauv kev tswj hwm kev lag luam vesicle tau ua rau tshawb xyuas nws txoj kev sib raug zoo rau kev txhim kho ntau yam kab mob (Table 1).
Yuav ua li cas Rab proteins ua hauj lwm thiab lawv lub luag hauj lwm nyob rau hauv cov kab mob tau kawm ntau nyob rau hauv lub hlwb ntawm lub paj hlwb, soj ntsuam lub luag hauj lwm ntawm neuronal lub neej voj voog, kev ua si, thiab intraneuronal deposits tsub zuj zuj [24-27]. Hauv cov kab mob neurodegenerative sib txawv, kev hloov pauv thiab kev tswj hwm lub luag haujlwm ntawm Rab proteins hauv cov txheej txheem pathological hauv cov neurons, ntawm qib mitochondrial, thiab glial cell dysfunctions tau tshawb xyuas. Hauv Alzheimer's, Parkinson's, Huntington Corea, Amyotrophic Lateral Sclerosis, thiab Charcot-Marie-Tooth kab mob [25], kev hloov pauv ntawm Rab proteins tau txheeb xyuas. Txawm hais tias kev hloov pauv ntawm Rab proteins tsis yog thawj qhov ua rau muaj tus kabmob hauv lawv txhua tus, txawm tias yog qhov tshwm sim. Rab7, Rab28, thiab Rab11 kev hloov pauv yog thawj qhov ua rau tus kab mob Charcot-Marie-Tooth thiab Rab39B hauv Parkinson's disease [28–31]. Cov teebmeem thib ob ntawm RabGTPases ntawm daim nyias nyias kev lag luam nws tus kheej tau pom nyob rau hauv ntau lwm yam kab mob (Saib kev tshuaj xyuas dav hauv 16). Ib qho piv txwv ntawm qhov nyuaj ntawm cov txheej txheem koom nrog hauv cov kev hloov pauv ntawm Rab proteins yog cov kev tshawb fawb tau ua los ntawm Parkinson's disease [32]. Txuas rau Rab39b kev hloov pauv, Rab29, Rab5a, thiab Rab7 tau raug txheeb xyuas nyob rau hauv keeb kwm yav dhau los ntawm Parkinson tus kab mob nrog Lewy lub cev [31]. Nyob rau hauv sib piv, Rab11 cawm ntau phenotypes, xws li tsub zuj zuj ntawm Lewy protein [33]. Kev tshawb fawb hauv kev tshuaj xyuas Rab thiab vesicular tsheb mechanisms tuaj yeem pab kom nkag siab txog dab tsi ua rau cov neurons ciaj sia thiab nws lub luag haujlwm hauv cov kab mob neurodegenerative.
Hauv cov kab mob plawv, cov ntaub ntawv tseem ceeb kuj tau txais. Kev nthuav qhia ntau ntxiv ntawm Rab1 hauv myocardium distorts subcellular localization ntawm cov protein thiab txaus ua rau mob plawv hypertrophy thiab tsis ua haujlwm [34]. Hauv myocytes, Rab9-dependent autophagosomes paub thiab cuam tshuam cov mitochondria puas, ua rau ischemia-reperfusion (IR) hloov pauv hauv oxidative phosphorylation, thaum kawg txo qis cardiomyocyte viability [35–37]. Hauv cov neeg mob ntshav qab zib uas muaj albuminuria, kev tshawb fawb ntawm genome-wide koom haum txheeb xyuas cov caj ces ntawm Rab38 cuam tshuam nrog albuminuria, qhia txog txoj hauv kev tshiab cuam tshuam rau albuminuria [38].
Hauv platelets, lawv qhov cuam tshuam ntawm hemostasis thiab thrombosis nrog rau cov ntaub so ntswg rov tsim dua tshiab, o, thiab metastasis los ntawm kev nqa, ntim, thiab tso tawm ntawm cov exosomes los ntawm cov vesicles khaws cia tau kawm ntau ntxiv vim lawv muaj peev xwm kho tau [39]. Lub luag haujlwm hauv phagocytosis rau engulf, tua, thiab txheej txheem txawv teb chaws lub cev thiab apoptotic hlwb thiab nthuav tawm antigens rau lub cev tiv thaiv kab mob tau raug txheeb xyuas tias ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob [40]. Hauv IR raug mob, phosphorylation-tswj polarization mechanism los ntawm Rab21 ntawm Rph3A yog ib qho tseem ceeb rau neutrophil adhesion rau endothelial hlwb thaum lub sij hawm inflammatory teb [41]. Hauvdaim siab, interferon regulatory factor 1 regulates Rab27a transcription and extracellular vesicle secretion, ua rau oxidized phospholipid activation ntawm neutrophils thiab tom qab mob hepatic IR [42].
Muab qhov tseem ceeb ntawm Rab GTPases hauv kev lag luam hauv daim nyias nyias, thiab qhov cuam tshuam ntawm cov txheej txheem no rau tib neeg kev noj qab haus huv [22], tej zaum kuj xav tsis thoob tias tsuas yog qee tus kab mob caj ces cuam tshuam nrog Rab tsis ua haujlwm. Qhov muaj nyob ntawm ntau yam Rab isoforms thiab txoj hauv kev ua lag luam ua rau tib neeg tsis tshua muaj kev cuam tshuam rau kev hloov pauv hauv ib tus neeg Rab-encoding noob.
3.1. Rab-Mediated Actions hauv Kev Noj Qab Haus Huv thiab Kab Mob hauv lub raum
Covlub raumyog ib qho tseem ceeb hauv nruab nrog cev los tswj lub homeostasis ntawm ntim kua thiab electrolytes los ntawm kev ua haujlwm ntawm cov hlwb tshwj xeeb ntawm ntau theem ntawm cov qauv. Dys-function ntawm ib qho ntawm cov no ua rau muaj kev cuam tshuam tsis zoo rau lwm tus, ua rau kev nce qib hauv kev txo qislub raum muaj nuj nqitsiv mus rau ib tug ChronicKab mob raum(CKD), uas muaj ntau heev nyob rau hauv cov pej xeem, nyob ib ncig ntawm 10 feem pua. Feem ntau cov cell hauv cov ntaub so ntswg thiab tshwj xeeb tshaj yog nyob rau hauv lublub raumpolarized thiab feem ntau muaj ob qhov sib txawv plasma membrane domains - ib qho apical thiab basolateral membrane - uas yog qhov tshwm sim ntawm kev lag luam polarized ntawm cov protein thiab lipids. Hauvlub raumglomerulus, podocytes yog cov hlwb sib txawv heev uas muaj lub luag haujlwm tseem ceeb hauv kev saib xyuas ntawm qhov pom kev cuam tshuam [53], kev koom tes nrog vascular endothelial thiab cov hlwb mesangial. Hauv cov tubules, cov hlwb muaj ntau lub tswv yim tshwj xeeb rau kev ua haujlwm sib txawv thiab cov neeg txhais lus endothelial-mesenchymal ua lub luag haujlwm tseem ceeb hauv cov txheej txheem o. Kev paub txog Rab GTPase nyob rau hauv cov khoom sib txawv ntawm cov cellularlub raumtau tsim, txawm hais tias qhov tseem ceeb ntawm kev noj qab haus huv thiab kab mob niaj hnub no tsuas yog txwv. Kev nce qib hauv kev nkag siab lub luag haujlwm ntawm Rab GTPase hauvraumtau txais los ntawm kev ntsuam xyuas cov kev qhia thiab kev ua ntawm exocyst complex nyob rau hauv kev loj hlob thiab kho ntawm tubular puas, txheeb xyuas cov kev hloov nyob rau hauv Rab proteins induced los ntawm tsawg zaus genetic nephropathy los yog kub siab, los yog ntsuam xyuas pathologic qhia nyob rau hauv cov qauv ntawm proteinuria, ob leeg glomerular thiab tubular. . Ib yam li ntawd, lub luag haujlwm hauv exosome secretion kuj tau kuaj xyuas. Kab lis kev cailub raum hlwbthiab hauv vivo qauv tau siv los tshawb nrhiav cov txheej txheem uas Rab proteins tau koom nrog. Piv txwv li, nephrocytes ntawm Drosophila, analogs ntawm podocytes, thiab tubular hlwb nyob rau tib lub sij hawm muab ib lub cuab tam los kuaj Rab zog los ntawm kev siv genetic manipulation. Hauv Table 2, cov ntsiab lus ntawm kev paub txog Rab kev koom tes hauvlub raumphysiology thiab pathological xeev tau nthuav tawm. Lub exocyst yog ib qho kev txuag heev yim-subunit protein complex koom nrog hauv lub hom phiaj thiab docking ntawm exocytic vesicles translocating los ntawm trans-Golgi network mus rau ntau qhov chaw hauvlub raumcev [54]. Muaj ntau txoj haujlwm ntawm exocyst hauv lub cevraumyog qhov tshwm sim ntawm ntau yam kev tswj hwm me me GTPases, koom nrog hauv thawj ciliognesis, cystogenesis, thiab tubulogenesis. Lub luag haujlwm ntawm kev kholub raumtubules epithelial hlwb tom qab ib tugmob hnyavmob raumkuj tau lees paub [55].
3.1.1. Podocytes
Fu li al., tau txheeb xyuas 27 qhov sib txawv ntawm Rabs hauv nephrocytes, kaum ib qhov ua haujlwm tau zoo thiab ntawm lawv, tsib qhov tseem ceeb los tswj kev ua haujlwm, thiab peb qhov tseem ceeb. Silencing Rab5 tau txheeb xyuas lawv lub luag haujlwm hauv kev tswj hwm endocytosis. Thaum ua tib yam hauv Rab7 thiab Rab 11, kev hloov pauv hauv cov protein degradation thiab membrane recycling tau pom. Raws li qhov tshwm sim ntawm kev ntsiag to cov noob no, kev cuam tshuam hauv lub koom haum vesicles, kev ncaj ncees ntawm cov teeb meem pom, thiab cov txheej txheem subcellular uas saib xyuas cov protein reabsorption tau pom [56]. Steroid-resistant nephrotic syndrome (SRNS) yog ib yam kab mob tsawg zaus uas 30 feem pua ntawm cov neeg mob hauv cov menyuam yaus yog vim muaj kev hloov pauv ntawm cov noob, nrog cov kab mob histological ntawm focal glomerulosclerosis (FSGS), ib tus mob tsis tshua muaj rau cov neeg laus. Hauv kev hloov pauv tsis zoo hauv TBC1D8B noob (TBC1domain tsev neeg), pom nyob rau hauv ob tsev neeg nrog X-txuas thaum ntxov SRNS, txo qis ntawm Rab11b GTPase-activating protein, soj ntsuam lub podocyte nyob rau hauv cov kev hloov ntawm vaj tse thiab kev tsiv teb tsaws chaw vim tsis muaj internalization thiab Cov txheej txheem rov ua dua tshiab [46] Kamp et al. piav qhia tsib tsev neeg ntxiv nrog qhov kev hloov pauv no thiab hauv tus qauv Drosophila, tau lees paub qhov cuam tshuam ntawm Rab11 hauv tus txheej txheem [57]. Lwm qhov kev hloov pauv tau txheeb xyuas tias yog vim li cas ntawm SRNS, nyob rau hauv GAPVD1 noob, (endosomal regulator), thiab tej zaum hauv ANKFY1 noob (Ankyrin Repeat thiab FYVE Domain Containing 1). Ob lub noob tau cuam tshuam nrog Rab5 thiab cov kev hloov pauv hloov pauv tau nce kev khi rau GTP-bound RAB5. Kev sib cuam tshuam ntawm GAPVD1 thiab nephrin, ib qho tseem ceeb ntawm cov protein nyob rau hauv lub diaphragm slit, qhia tias endocytic kev lag luam ntawm nephrin tuaj yeem ua lub luag haujlwm hauv RAB 5- kho mob pathogenesis ntawm SRNS [45].
3.1.2. Lub raum Tubules
Tubular ua haujlwm, feem ntau yog cov koom nrog hauv cov protein reabsorption, feem ntau cuam tshuam los ntawm kev hloov pauv hauv vesicular tsheb. Nyob rau hauv lub fawn-hooded hypertensive nas, ib tug qauv ntawm hypertension-koom nrogmob raum, Rab38 cuam tshuam rau urinary protein excretion nyob rau hauv proximal tubule. Siv cov kab mob sib kis kab mob LLC-PK1 hlwb, Rab38 mRNA knockdown txo endocytosis ntawm colloidal kub-coupled albumin [49]. Dhau li ntawm lub luag haujlwm ntawm Rab38 hauv cov hlwb epithelial tubular, lub luag haujlwm tseem ceeb ntawm Rab7 kuj tau txheeb xyuas los ntawm kev tiv thaiv kev txhim kho ntawm endothelial mesenchymal hloov (EMT) thiab apoptosis thaum albumin overload raug ntxias. Lub overload ntawm albumin nyob rau hauv tubular cell-induced activation ntawm MMP-2, matrix metalloproteinase-2, degrades hom IV collagen thiab txo cov thickening ntawm tubular basal membrane. Rab7 overexpression txo MMP-2 kev ua haujlwm khaws cia cov tubular basal membrane qauv. Qhov tshwm sim ntawm txoj kev tshawb no qhib qhov muaj peev xwm ua kom ua rau Rab7 yuav ua rau muaj txiaj ntsig zoo los tiv thaiv kev cuam tshuam ntawm overload ntawm cov protein nyob rau hauv intratubular flufluid txo EMT, xws li tshwm sim hauv ntshav qab zib nephropathy [50]. Tsis tas li ntawd, Slp2-a, tus tsim tawm ntawm Rab27A, tswj hwm apical lub hom phiaj ntawm podocalyxin thiab nws tus khub khi, ezrin, hauv kev hais kwv txhiaj nrog Rab27A. Cov kws sau ntawv tau tsim cov qauv ntawm claudin{18}} qhia los ntawm kev thauj khoom ntawm podocalyxin mus rau qhov chaw apical los ntawm kev ua haujlwm ntawm Slp2-a–Rab27A complex [51], uas ua rau muaj cov protein ntau nruj. .
Thaum kawg, lub luag haujlwm ntawm Rab proteins nyob rau hauv lub tubule sau tau raug kawm. Aquaporin yog vasopressin tswj cov dej channel protein ua lub luag haujlwm rau osmotic dej reabsorption los ntawm kev sau cov ducts. Nyob rau hauv lub xub ntiag ntawm vasopressin, Rab7 thiab vacuolar protein sorting 35 (Vps35) koom nrog AQP2 sorting nyob rau hauv thaum ntxov endosomes nyob rau hauv lub tsheb tej yam kev mob thiab apical membrane trafficking [58].
qhov twg yuav cistanche
3.1.3. Exosome Tso
Qhov cuam tshuam ntawm Rab proteins hauv exosome tso tawm kuj tau soj ntsuam nrog Rab27 ua lub luag haujlwm tseem ceeb. Ob qhov kev tshawb fawb tsis ntev los no qhia tau tias inhibiting lossis activating Rab27 kev qhia ua rau txo qis lossis nce hauv exosome tso tawm los ntawm podocytes. Hauv thawj qhov kev tshawb fawb no, overexpression ntawm KIBRA stabilized Rab27, zam nws degradation ntawm txoj kev ubiquitin-proteasome [59]. Nyob rau hauv qhov thib ob, nyob rau hauv ib tug qauv ntawm inflammatory teb rau proximal tubular epithelial hlwb, khob tawm Rab27a inhibited lub inflammatory ntau dhau los ntawm txoj kev CHAC1 / NF-κB. Qhov no yog vim qhov sib txuam hauv cov cell ntawm miR-26a, uas yog li ncua kev loj hlob ntawm cov ntshav qab zib.mob raum [52].
3.2. Rab-3A/Rabphilin-3A Complex inKab mob raum
Hauv kev tshawb fawb txog noob caj noob ces, peb pab pawg tau txheeb xyuas SNPs cuam tshuam txog kev pheej hmoo los tsim microalbuminuria los ntawm kev siv cov ntaub ntawv sib txuas ntawm cov noob caj noob ces thiab cov metabolomic los ntawm cov pej xeem, nrhiav kev koom tes ntawm polymorphism ntawm RPH3A gene thiab UAE [60]. Tsis ntev los no, hauv cov ntaub ntawv los ntawm Strong Heart Study, tag nrho ntawm 277 qhov sib txawv tau sau tseg hauv cov noob RPH3A, RPH3AL (Rabphilin 3A nyiam), RAB3IL1 (RAB3A cuam tshuam cov protein zoo li 1), thiab RAB27A muaj rau kev koom tes nrog kev tsom xam nrog UAE thiab GFR kev nce qib. dhau sijhawm. Siv cov qauv sib xyaw ua ke los suav txog kev sib raug zoo ntawm tsev neeg thiab kev kho rau cov neeg muaj peev xwm confounders, polymorphisms ntawm RAB3IL1 thiab RPH3A tau pom tias muaj kev cuam tshuam tseem ceeb nrog kev nce qib ntawm UAE thiab GFR qib (cov ntaub ntawv tsis tau tshaj tawm). Tsis tas li ntawd, ib qho kev tshawb fawb dhau los ntawm Framingham pawg kuj tau qhia txog kev koom tes ntawm UAE thiab RPH3A [61].
Nyob rau hauv 2003, Rastaldi et al. tshawb xyuas Rph3A thiab Rab3A raws li cov players ua tau hauv podocyte biology. Raws li qhov Rph3A khi rau Rab3A, nws yog ib qho nyuaj rau kev docking ntawm synaptic vesicles rau lawv lub hom phiaj membrane thiab uas khi nrog cytoskeletal proteins nyob rau hauv neurons, vesical thiab cytoskeletal tseem ceeb heev rau podocyte homeostasis [47]. Cov complex Rab3A-Rph3A tau pom nyob rau hauv cov neurons thiab cov qauv neuroendocrine zoo li qub.lub raumlos ntawm nas, nas, thiab tib neeg nyob rau hauv podocytes nyob ib ncig ntawm vesicles muaj nyob rau hauv cov txheej txheem ko taw [62,63]. Tsis tas li ntawd, nyob rau hauv tib neeg biopsies ntawm cov neeg mob proteinuric nrog focal thiab segmental glomerulosclerosis, qhov nce ntawm Rab3A-Rph3A qhia kuj tau txheeb xyuas [47]. Lub luag haujlwm muaj peev xwm ntawm cov molecules hauvlub raumkev puas tsuaj tau kawm ntxiv los ntawm tib pab pawg hauv cov qauv ntawm Rab3A knockout nas nrog cov khoom noj muaj qabzib siab. Cov nas knockout tsim hloov pauv podocyte actin plasticity nrog podocyte puas thiab proteinuria. Tsis tas li ntawd, nyob rau hauv cov qauv nrog kev noj zaub mov kom siab,lub raumCov kab mob zoo ib yam li cov neeg mob ntshav qab zib nephropathy tau tsim [64].
Peb pab pawg hauv kev ua haujlwm tsis ntev los no tau txheeb xyuas tias Rph3A tau qhia thiab colocalized nrog cov cim molecular ntawm endocytic thiab exocytic txoj hauv kev pericardial nephrocytes ntawm Drosophila melanogaster. Nephrocyte yog ib lub cell uas ua ke nrog podocyte thiablub raumproximal tubule ua haujlwm thiab koom nrog hauv kev tshem tawm cov khoom pov tseg los ntawm hemolymph thiab Malpighian tubules, ib qho qauv suav tias yog qhov sib piv raulub raumcev system [48] Muaj ob qhov sib txawv nephrocyte cov neeg: lub garland cell nephrocytes nyob ib ncig ntawm txoj hlab pas (binucleate) thiab pericardial nephrocytes (mononucleate) nyob nrog lub plawv, ob qho tib si ua haujlwm, ua haujlwm, thiab molecularly zoo ib yam li tib neeg podocytes [65].
Ntau qhov kev tshawb fawb qhia tias txoj hauv kev endocytic ua lub luag haujlwm tseem ceeb hauv kev txhim kho, kev saib xyuas, thiab kev puas tsuaj ntawm cov podocyte thiab tuaj yeem ua rau muaj kev hloov pauv hauv cell morphology [66-68]. Rph3A cuam tshuam txo qhov kev qhia ntawm Rab3a thiab Drosophila ortholog ntawm kev hloov pauv hloov pauv Krüppel-zoo li factor 15 (KLF15) yog zinc-fifinger transcription factor tau nthuav tawm hauv glomeruli thiab interstitial hlwb. Nws muaj lub luag haujlwm tiv thaiv hauv cov qauv proteinuric, los ntawm kev txo cov tubular thiab podocyte raug mob,lub raumfifibrosis, thiab mesangial lesion. Cov kev raug mob txo qis no txhawb kev hloov pauv hauv txoj hauv kev endocytic uas thaum kawg poob txoj hmoo ntawm tes [69]. Kev cuam tshuam morphological ntawm nephrocytes tau pom nyob rau ntau theem: (a) hauv qab daus membrane cuam tshuam, thiab (b) cytoskeletal hloov kho ua rau tsis muaj labyrinthine channel thiab nephrocyte poob (Daim duab 2).
Rph3A cuam tshuam kuj cuam tshuam rau kev qhia cov noob ncaj qha rau hauv cov qauv nephrocyte thiab kev ua haujlwm. Proteins Sns thiab Kirra, tib neeg nephrin, thiab neph1 orthologues, raws li, uas cuam tshuam los ntawm lawv cov extracellular domains los ua nephrocyte diaphragm [70], raug txo qis (silenced). Qhov tsis muaj Sns qhia ua rau muaj qhov txo qis ntawm nephrocyte tus lej, sib haum nrog cov kev tshawb fawb tsis ntev los no uas tau sau tseg qhov tseem ceeb ntawm cytoplasmic Sns hauv kev tswj hwm intra-nephrocyte actin lub koom haum [71]. Tsis tas li ntawd, Cubilin-Amnionless system, ua tus saib xyuas endocytosis ntawm cov protein me me thoob plaws lub labyrinthine channels [72], kuj raug cuam tshuam los ntawm Rph3A cuam tshuam. Kev txo qis hauv cov protein kom tsawg los ntawm nephrocyte tau tshwm sim los ntawm kev txo qis hauv Cubilin qhia thiab vesicular trafficking cuam tshuam los ntawm qib qis ntawm KLF15 [48] (Daim duab 2). Ob lub tshuab, Sns proteins, thiab Cubillin proteins, tuaj yeem hloov pauv los ntawm kev txo qis hauv cov noob qhia lossis mislocalization ntawm ib qho ntawm lawv cov khoom. Peb txoj kev tshawb fawb qhia txog lub luag haujlwm ntawm kev tswj hwm kev sib raug zoo ntawm cytoskeletal Cheebtsam thiab nephrocyte diaphragm proteins uas yog qhov tseem ceeb rau qhov loj me thiab kev saib xyuas raws li tus nqi thiab muab cov ntaub ntawv los txhawb cov txiaj ntsig yav dhau los hauv Rab3A knockout nas qauv, uas ua rau muaj proteinuria thiablub raumkev tsis txaus ntseeg [64].
Ib txhij, peb pab pawg tau txheeb xyuas qhov cuam tshuam ntawm cov piam thaj siab thiab angiotensin II ntawm Rab3A-Rph3A system hauv tib neeg tsis txawj tuag podocytes thiab hauv cov zis cell pellets los ntawm cov neeg mob ntshav siab thiab ntshav qab zib [73]. Peb cov txiaj ntsig tau qhia tias Rab3A Rph3A qhov system tuaj yeem koom nrog cov kev hloov pauv tau pom nyob rau hauv cov neeg raug mob podocytes thiab tias lub tshuab yuav raug qhib kom txo tau kev puas tsuaj los ntawm kev thauj mus los ntawm vesicular los ntawm cov kab ke no. Thaum kawg, cov ntaub ntawv ua ntej los ntawm peb pab pawg pom tau tias Rph3A kuj tau hais tawm hauv Drosophila myocardiocytes, thiab Rph3A ntsiag to muaj kev cuam tshuam zoo rau lub koom haum ntawm fibers thiab kev ua haujlwm ntawm lub plawv [74]. Hauv cov ntsiab lus, Rab3A-Rph3A system plays lub luag haujlwm hauvraumkev puas tsuaj mechanisms. Txawm hais tias nws tuaj yeem ua lub luag haujlwm hauv kev ua haujlwm ntawm lub cev tsis zoo, dhau los ua qhov kev tshawb fawb zoo nkauj uas xav tau kev saib xyuas yav tom ntej.
4. Cov lus xaus
Rab-GTPases yog cov proteins uas cuam tshuam kev thauj mus los ntawm cov vesicles uas nqa cov khoom thauj hauv thiab tawm ntawm cov hlwb thiab cov organelles. Rabs muaj lub luag haujlwm tseem ceeb hauv kev tswj hwm vesicle kev lag luam hauv cov hlwb, uas yog ib qho tseem ceeb rau ntau cov txheej txheem ntawm tes, xws li kev loj hlob ntawm tes, khoom noj khoom haus ntawm tes, lub cev tiv thaiv kab mob, mitosis, thiab apoptosis. Yog li, Rabs yog lub hom phiaj molecular hauv ntau yam kab mob xws li mob qog noj ntshav, kab mob plawv, kab mob tiv thaiv kab mob, thiab kab mob neurodegenerative. Txawm li cas los xij, qhov cuam tshuam ntawm kev hloov pauv Rabs qhia tsis tshua nkag siab hauv cov kab mob tshwj xeeb uas vesicular trafficking muaj qhov cuam tshuam loj rau lawv cov qauv thiab kev ua haujlwm, xws li hauv lub cev.raum.Cov kev tshawb fawb tsis ntev los no tau qhia txog qhov tseem ceeb ntawm Rab3A-Rph3A complex hauv morphology, cell poob, thiab fifiltration muaj nuj nqi hauvraum. Tsis tas li ntawd, tsis ntev los no nyob rau hauv lub plawv Drosophila, ua rau nws ib tug tshiab molecular neeg uas ua ntawv nyob rau hauv lub pathogenesis ntawmlub raumthiab mob plawv tsis ua hauj lwm thiab ua ib qho kev txaus siab tam sim no nrog cov kev siv tshuaj kho mob. Nyob rau lub sijhawm no, ntau cov lus nug txog kev ua haujlwm tiag tiag tseem tsis tau teb thiab yuav xav tau kev tshawb fawb yav tom ntej.
cistanche muag
