Intertwined Thiab Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, Thiab Kab Mob Part 5
Apr 10, 2024
3.1.2. MCS-Mediated ER Dynamics
Ntxiv rau cov tubule txuas ntxiv uas tau tsav los ntawm cov motors ncaj qha ntawm ER daim nyias nyias, ERdynamics tuaj yeem tshwm sim los ntawm ER membrane cov chaw sib cuag nrog cov endosomes ntxov thiab lig, lysosomes, thiab mitochondria [22,26,38,74,75,84–{{6} },204,219,220] uas txav raws microtubules.
Kev tshawb fawb tau pom tias cov kua qaub hydrolase hauv lysosomes tuaj yeem rhuav tshem cov proteins thiab hloov mus rau hauv cov amino acids, uas tuaj yeem siv los ntawm cov hlwb los tsim cov proteins tshiab. Cov txheej txheem no yog ib qho tseem ceeb rau kev kawm thiab kev nco, vim hais tias protein synthesis yog ze ze rau kev tsim ntawm lub cim xeeb.
Tsis tas li ntawd, lysosomes tseem tuaj yeem ua kom cov hlwb noj qab haus huv los ntawm kev rhuav tshem cov khib nyiab ntawm tes thiab cov khoom tsis zoo thiab tshem tawm cov khib nyiab thiab co toxins los ntawm lub hlwb. Cov txheej txheem no kuj tseem ceeb heev rau kev tiv thaiv kev ciaj sia thiab kev ua haujlwm ntawm neurons. Neurons yog peb lub hlwb thiab lawv ua lub luag haujlwm tseem ceeb hauv kev kawm thiab kev nco. Yog tias cov neurons cuam tshuam los ntawm cellular pov tseg thiab cov khoom tsis zoo, lawv txoj haujlwm thiab kev muaj peev xwm ciaj sia yuav raug cuam tshuam loj heev, cuam tshuam rau kev tsim thiab khaws cia ntawm kev nco.
Yog li ntawd, kev tswj hwm kev ua haujlwm thiab kev noj qab haus huv ntawm lysosomes yog qhov tseem ceeb rau kev txhim kho kev nco thiab tiv thaiv kev ciaj sia thiab kev ua haujlwm ntawm neurons. Yuav ua li cas tswj lysosome muaj nuj nqi thiab kev noj qab haus huv? Ua ntej ntawm tag nrho cov, peb yuav tsum tau xyuam xim rau kev noj cov as-ham, tshwj xeeb tshaj yog kev noj cov zaub mov tseem ceeb xws li cov protein; thib ob, peb yuav tsum tswj kom txaus pw tsaug zog thiab tawm dag zog; Thaum kawg, peb yuav tsum zam kom tsis txhob muaj kev ua neej nyob tsis zoo xws li nyob lig kom txo tau lub neej kev ntxhov siab thiab lub nra hnyav.
Hauv cov ntsiab lus, kev sib raug zoo ntawm lysosomes thiab kev nco yog ze heev. Los ntawm kev tsom mus rau kev tswj hwm lysosomal muaj nuj nqi thiab kev noj qab haus huv, peb tuaj yeem txhim kho kev nco thiab tiv thaiv neuronal ciaj sia thiab ua haujlwm, yog li txhawb kev noj qab haus huv thiab kev loj hlob ntawm lub cev. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv cov kab mob. kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm muaj peev xwm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv kev loj hlob ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.
Nyem Paub txhawm rau txhim kho lub cim xeeb luv luv
Qhov no yog ib qho piv txwv ntawm cov txheej txheem hu ua 'hitchhiking', qhov twg ib qho organelle muab lub cev muaj zog thiab tsav lub zog ntawm lwm cov khoom thauj uas tsis yog txav los ntawm nws tus kheej [38,221,222].Early ua haujlwm ntawm ER tubule txav tau txheeb xyuas qhov sib txawv ntawm morphologically motiledomains ntawm cov lus qhia ntawm qee qhov txav ER tubules [182,191].
Txawm li cas los xij, muaj pov thawj tseeb los ntawm kev xa cov teeb pom kev zoo thiab DiOC6 daim ntawv lo uas ER tubules lawv tus kheej tuaj yeem hloov mus ncaj qha nrog microtubules, tsis tas yuav muaj kev sib tw nrog lwm cov kabmob [19,182,183,190].
Ib ncig ntawm ib nrab ntawm Rab5-zoo endosomes hauv Cos-7 hlwb tau txuas nrog ER thaum lub sijhawm ua haujlwm [75], thiab thaum pom ntawm tus ncej qis (1 thav duab ib 1.5 s) tshwm sim tsawg dua li ER-koom nrog lysosomes [219], thiab tsawg dua yuav ua rau ER tubule mobility [26].
Txawm li cas los xij, kev ua neej nyob ntawm tus nqi nrawm uas xav tau los txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm
Raws li thaum ntxov endosomes txav mus rau qhov chaw ntawm tes, tsav los ntawm dynein [74,223], hitchhiking ntawm endosomes thaum ntxov yuav suav rau qee qhov dynein-dependent ER tubule extensions [20].
Yuav ua li cas dynein thiab kinesins raug recruited mus rau endosomes thaum ntxov, thiab lub luag hauj lwm ntawmkinesin -1 nyob rau hauv lawv lub zog, yog tsis to taub tag nrho. Cov hauj lwm tsis ntev los no qhia tias 30-50% ntawm ER tubule extension txheej xwm yog tsav los ntawm hitchhiking ntawm lig endosomes/lysosomes tsiv raws microtubules, thaum 40% ntawm tubulesmoved raws microtubules ntawm nws tus kheej, thiab cov seem tau kho los ntawm TACs ordTACs (saib hauv qab) [26,38,219].
Kuj ceeb tias, yuav luag tag nrho cov lysosomes tau txuam nrog thiab tsiv nrog, ER network [219]. Lysosomes uas tau pom ua ntej, thaum lub sijhawm, thiab tom qab qhov kev tshwm sim hitchhiking tau pom qeeb thaum txuas nrog ER tubules [204,219], tej zaum vim tias tsis tshua muaj kev cuam tshuam lub zog tsim los ntawm lysosomalmotors thaum tsis txuas ER tubules.
Ob ER-neeg nyob hauv cov proteins koom nrog hauv phospholipid synthesis, PIS, thiab CEPT1, uas yav dhau los tau pom tias yog nyob rau ntawm cov lus qhia ntawm motile tubules nrog rau Rab10 [7], tau txuam nrog LE / lysosome hitchhikingevents [26].
Ib zaug ntxiv, dynein thiab kinesin-1 yog cov motors loj tsav tsheb lig endosome/lysosomemovement, thiab muaj ntau txoj hauv kev uas lawv tau txais thiab tswj, qee qhov cuam tshuam nrog ER (saib hauv [128,129]). Dynein tuaj yeem nrhiav tau ntawm RILP thiab Rab7 (nyob rau hauv muaj cov roj cholesterol siab); ALG2 thiab TRPML1 ( tswj los ntawm PI (3,5) P2 thiab calcium); los yog JIP4 thiab TMEM55B (nce los ntawm kev tshaib plab, uas nce TMEM55B transcription ntawm mTORC1) [128,129]. Kinesin-1 raug xaiv los ntawm SKIP thiab Arl8 ( tswj hwm los ntawm BORC), lossis FYCO1 thiab Rab7 ( tswj hwm los ntawm PI(3)P thiab koom nrog protrudin ntawm ER: saib hauv qab), thiab ob qho kev sib txuas yog los ntawm KLCs [128,129].
Ib lo lus nug qhib yog seb cov txheej txheem ntau yam ua haujlwm nyob rau hauv tib lub cev, lossis seb puas muaj kev xaiv spatial (piv txwv li, ntawm cov membrane subdomains), los yog hloov nyob ntawm seb cov txheej txheem metabolic, lossis lwm yam khoom siv.
Yog tias tsuas yog 30-50% ntawm ER tubules txav mus rau hauv kev koom tes nrog lig endosomes / lysosomes, qhov no tseem ceeb npaum li cas rau ER lub koom haum tag nrho? Ob qhov kev tshawb fawb tsis ntev los no tau ua pov thawj tias hauv Cos-7 hlwb tsawg kawg, cov lus teb yog heev.
Kev cuam tshuam ER-late endosomeMCSs los ntawm RNAi-mediated depletion ntawm VAPA (uas khi ORP1L rau thauj tog rau nkoj LE rau ERvia Rab7: [128]) kuj cuam tshuam ER morphology thiab txo qis ntawm ER tubules thiab network complexity, tshwj xeeb tshaj yog nyob rau hauv periphery [26,26]. qhov knockdown ntawm tag nrho ER VAP tsev neeg cov tswv cuab (VAPA, VAPB, thiab MOSPD2) muab qhov muaj zog phenotype [26].
Tsis tas li ntawd, kev tswj xyuas cov motors tam sim no nyob rau hauv lig endosomes / lysosomes muab ib qho txiaj ntsig txhais tau tias ua rau sab hauv lossis sab nraud endosome txav, uas ua rau txo qis lossis nce peripheral ER tubules [26,219] thiab network dynamics [26].
Interestingly, qhov depletion ntawm SKIP lossis Arl8 ua rau muaj kev hloov pauv loj hauv ER network, qhia tias qhov no yog txoj hauv kev loj rau kinesin-1 recruitment rau cov txheej txheem no, tsis yog protrudin / FYCO1 [219].Protrudin, cov khoom ntawm ZFYVE27 noob. , yog ib tug multispanning transmembraneER protein uas muaj plethora ntawm interactors, ob qho tib si ntawm ER thiab thaum kawg endosomes.
Atthe ER, nws khi rau ER shaping proteins atlastin, REPs 1 thiab 5, reticulons 1, 3, thiab 4, thiab tseem cuam tshuam nrog VAP ntawm FFAT motif ([224]; tshuaj xyuas hauv [225]). Nws kuj tseem tuaj yeem khi rau cov endosomes lig dhau los ntawm nws Rab-binding domain, uas khi Rab7-GTP, thiab FYVE(Fab-1, YGL023, Vps27, thiab EEA1) domain, uas khi rau lub sijhawm endosomally enrichedphosphatidylinositol. 3-phosphate (PI3P) [204,225].
Qhov tseem ceeb, nws tseem khi rau txhua tus neeg hauv tsev neeg KIF5, txawm hais tias kev sib cuam tshuam yog qhov muaj zog tshaj plaws nrog KIF5A [226], uas yog kev xav txog ob qho tib si protrudin thiab KIF5A (tab sis tsis yog KIF5B lossis C) tuaj yeem ua rau muaj kab mob spasticparaplegia thaum hloov pauv (Table 1).
Tshaj tawm ntawm cov protein ntau dhau los ua rau tsim cov protrusions hauv cov hlwb tsis muaj polarised [226], yog li protrudin lub npe [225], thaum siRNA-mediated depletion coj mus rau qhov nthuav dav ntawm CLIMP63-cov ntawv sau zoo li thaj chaw rau hauv lub cell periphery [224].Rau protrudin lub peev xwm los khi rau qhov kawg endosome, Raiborg thiab cov neeg ua haujlwm tau tshawb xyuas yog tias nws tau koom nrog hauv MCS tsim thiab pom tias yog qhov tseeb [204].
Tsis tas li ntawd, overexpression ntawm protrudin coj mus rau ib tug tsub zuj zuj ntawm lig endosomes / lysosomesat lub cell periphery, ib tug phenotype uas yav tas los tau pom rau FYCO1, lwm PI3Pand Rab7-binding protein, thiab uas tau pom muaj kev cuam tshuam nrog protrudin [204] .
Kev xav txog FYCO1 thiab protrudin hauv cov hlwb muaj sia qhia tau tias txav FYCO1- cov kab mob lateendosomes zoo cuam tshuam nrog protrudin ntawm ER, ncua lossis qeeb thaum lawv ua qhov no, tom qab ntawd tshem tawm thiab txav tawm sai dua. Protrudin khi KIF5 thiab FYCO1 bindsKLC, thiab cov lus qhia ntawm protrudin nce tus nqi ntawm KIF5 pom muaj feem xyuam nrog FYCO1, ua rau cov qauv uas kinesin tau dhau los ntawm protrudin mus rau FYCO1 ntawm lateendosome thaum lub sij hawm ER-late endosome koom haum, yog li activating lig endosome movementonce lawv tawg. dawb ntawm ER.
Thaum cov qauv no txaus siab, xav tau cov ntaub ntawv pov thawj ntau dua.Qhov tseeb tab sis yog tias ob qho tib si protrudin thiab FYCO1 tseem ceeb rau axon txuas ntxiv [129,195,204,227]. Protrudin thiab FYCO1-kev kho mob lig endosome translocation mus rau lub cell periphery kuj tau pom tias yog ib qho tseem ceeb rau invadopodia tsim, qhov twg lateendosomes xa cov matrix protease MT1-MMP rau secretion, uas yog tsim nyog rau lub cell migration [205 ].
Qhov tseem ceeb, txoj haujlwm lig endosome / lysosome yog tswj los ntawm kev noj zaub mov zoo, xws li qib roj cholesterol thiab amino acid, uas ua rau tswj cov dynein thiab kinesin-1kev ua haujlwm lossis kev ua haujlwm [128,129,228].
Cov kev cai no tsis ntev los no tau pom tias muaj kev cuam tshuam loj heev rau ER dynamics thiab kev faib tawm hauv cell [26,219]. Serum starvationled mus rau ib tug tsawg mobile ER network thiab txo lig endosome / lysosome motility, ua rau ib tug tsawg complex ER network nyob rau hauv lub cell periphery nrog tsawg tubule junctions [26]. Lu thiab cov neeg ua hauj lwm tau pom tias kev tshaib plab 4 h serum ua rau lig endosome / lysosome pawg, thiab txo qhov feem ntawm tubular ER, ib yam li cov cholesterol enrichment [219].
Hauv qhov sib piv, 24-teev tshaib plab lossis txo cov roj cholesterol ua rau muaj kev cuam tshuam ntawm cov endosomes uas tsis muaj kev cuam tshuam rau ER tubules [219].Qhov kev sib txuas ntawm cov protrudin-mediated ER-endosome/lysosome kuj cuam tshuam los ntawm kev noj zaub mov zoo. Lub neuronal isoform ntawm carnitine palmitoyltransferase 1, CPT1C, isan ER protein uas tswj los ntawm malonyl-CoA qib thiab hloov pauv hauv HSP [228].
Kev ua haujlwm tsis ntev los no tau qhia tias CPT1C xav tau rau kev loj hlob neuronal thiab tswj kev thauj mus los ntawm cov endosomes / lysosomes lig mus rau axon taub, thiab qhov no xav tau nws lub peev xwm los khi rau malonyl-CoA [228].
Nws cuam tshuam nrog protrudin, thiab qhia nws hauv HeLa hlwb nce qhov feem ntawm sab nraud-tsav FYCO1- sau npe lig endosomes yog malonyl-CoA tau tshwm sim, tab sis txo qis kev txav mus rau hauv qab tswj theem yog malonyl-CoA depleted.
Txawm li cas los xij, tsis zoo li protrudin, CPT1C tau tshwm sim, tab sis tsis muaj txiaj ntsig, ntawm ER-lysosome kev sib cuag, qhia tias nws tswj cov protrudin-FYCO1-kinesin-1 kev sib cuam tshuam ntau dua li kev koom tes ncaj qha. Cov kws sau ntawv qhia tias nyob rau hauv muaj malonyl-CoA, CPT1C txhawb kev hloov pauv ntawm kinesin-1 los ntawm protrudin mus rau FYCO1 ntawm lig endosomes / lysosomes, yog li txhawb nqa lawv sab nraud txav hauv cov neurons [228].
Txawm li cas los xij, raws li tau hais los saum toj no, tus qauv hloov pauv kinesin no yuav tsum tau kuaj ntxiv. Mitochondria paub tias muaj kev cuam tshuam nrog ER hauv cov hlwb nyob [22], thiab cov mitochondria tuaj yeem txuas ER tubules [22,38]. ER-sociated mitochondria yog qhov nyiam tshaj plaws hauv cheeb tsam rau acetylated microtubules [22], uas yog qhov nyiam taug qab rau kinesin -1(eg, [229]), uas yog lub cev muaj zog rau ob qho tib si mitochondria (piv txwv li, [230]) thiab ER.
Mitochondriawere kuj pom muaj kev cuam tshuam nrog lysosomes, thiab cov lysosome txav tuaj yeem rub tawm athin tubule los ntawm mitochondrion [38]. Raws li cov tubules nyias nyias tau pom los txuas ntxiv los ntawm mitochondria ntawm cov ntsiab lus ntawm ER kev sib cuag los ntawm kev ua ntawm KIF5B thiab nws cov mitochondrialreceptor Miro1 [230], nws ua rau cov lus nug txog seb PDZD8- ntxias peb-wayMCSs ntawm ER, lig endosomes , thiab mitochondria tuaj yeem koom nrog ob txoj haujlwm.
Txawm li cas los xij, qhov kev cuam tshuam nyuaj no tseem ceeb ua rau cov organelles [126].
MCSs tseem ceeb heev rau ntau yam ntawm ER muaj nuj nqi, metabolism, thiab tag nrho cov dynamics. Qhov no ua rau nws nyuaj los txhais cov kev hloov pauv tau pom hauv qab no cov kev sim tsim los cuam tshuam ib feem ntawm MCS txoj haujlwm.
Qhov no yog ua piv txwv los ntawm kev sim qhov twg Rab7a muaj nuj nqi-xav tau rau lig endosome/lysosome MCS, thiab koom nrog kev nrhiav neeg ua haujlwm ob leeg kinesin-1 thiab dynein rau endosomes- tau cuam tshuam. Rab7a depletion, lossis kev qhia ntawm GDP-xauv Rab7a, coj mus rau qhov sib sau ntawm CLIMP63- sau ntawv zoo li ER ntawm lub cell periphery, thiab ua kom cov lus teb ER kev ntxhov siab [231].
Mateus et al.hypothesize tias kev hloov pauv ntawm cov qauv yog tshwm sim los ntawm ER kev ntxhov siab, tsis yog kev hloov pauv hauv ER dynamics [231]. Qhov tseeb, muaj ntau txoj hauv kev uas kev ntxhov siab tuaj yeem cuam tshuam MCS thiab theER (saib hauv [85]). Kev soj ntsuam ER qib kev ntxhov siab yuav yog ib qho tseem ceeb ntawm kev tswj xyuas yav tom ntej (xws li, [219]).
3.1.3. Motor-Independent ER-Microtubule Interactions
Nws tau pom tseeb los ntawm cov kev tshawb fawb thaum ntxov uas peb hom ER-microtubule kev sib cuam tshuam muaj nyob: motor-driven translocation of ER tubules, static interactions, and the attachment of ERtubules to grow microtubules [23].
Kev sib cuam tshuam tom kawg tsav tubule txuas ntxiv los ntawm kev tsim ntawm 'tip attachment complexes', lossis TACs, thawj zaug pom hauv Xenopus qe rho tawm [232].Nyob rau ntau hom kab lis kev cai, lub cev muaj zog zawv zawg tau pom los ua ntej tshaj TACsand kev sib cuam tshuam zoo li qub ntawm ER tubule. cov lus qhia thiab microtubules [20,21,23,38], txawm hais tias feem pua ntawm cov xov tooj sib txawv [21].
TACs muaj cov transmembrane ER proteinSTIM1 (stromal interactivity molecule 1), uas cuam tshuam nrog MT plus-end-trackingprotein EB1 [21]. STIM1 cuam tshuam nrog Orai1 ntawm cov plasma membrane thaum depletion ntawm ERcalcium khw muag khoom kom tso cai rau cov calcium hloov ntawm sab nraum lub cell mus rau hauv ER (saib Tshooj 2.2.5).Qhov zoo siab, ua rau cov txheej txheem no tiv thaiv STIM1 tip tracking [21].
Thaum lub xub ntiag ntawm TAC tsis hloov tus nqi ntawm microtubule kev loj hlob thiab shrinkage, nws txo qhov zoo li ntawm microtubule raug kev puas tsuaj (pib depolymerize) [232]. ERtubules kuj tseem tuaj yeem txuas ntxiv los ntawm kev txuas mus rau lub depolymerising microtubule ntawm dTAC [38]; qhov muaj pes tsawg leeg ntawm ER dTACs tsis paub.Vim li cas muaj ob txoj hauv kev thauj ER mus rau ntawm lub cell periphery?
Nyob rau hauv rooj plaub ntawm Xenopus embryos, txawm hais tias kinesin -1 yog tam sim no nyob rau hauv ER, nws tsis nquag mus txog rau tom qab kev loj hlob [187]. Hloov chaw, ER network faib thoob plaws hauv cytoplasm los ntawm kev sib xyaw ua ke ntawm dynein rub nws mus rau lub nucleus thiab centrosome, thiab TACsextending nws sab nraud li microtubules ppolymerize [184]. Hauv kab lis kev cai, TACs yuav ua kom lub ER mus txog sab xis ntawm lub xov tooj ntawm tes.
Hauv qhov sib piv, kinesin -1 qhov kev nyiam rau cov microtubules ruaj khov raws li kev taug qab, tej zaum vim tias lawv tsis tshua muaj MAP7 khi rau lawv qhov chaw, txhais tau tias nws hloov tsis zoo mus rau qhov kawg ntawm cov tshiab polymerized microtubules [229].
Lub luag haujlwm tseem ceeb rau STIM1-EB1-kev kho ER hauv cheeb tsam tau pom muaj nyob hauv neuronal growthcones, qhov twg STIM1 xav tau rau kev taw qhia ntawm microtubules thiab ER uas yog qhov tseem ceeb rau lub khob loj hlob kom txav mus rau qhov kev loj hlob zoo gradient [ 233] ib.
For more information:1950477648nn@gmail.com
