Intertwined Thiab Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, Thiab Kab Mob Part 3

2.2.4. MCSs: Lipid Exchange

Cov lipid synthesis tshiab yuav tsum tau xa los ntawm lipid synthesis subdomains ntawm ER mus rau lawv qhov chaw kawg. Txhua daim nyias nyias organelle muaj ib qho lipid muaj pes tsawg leeg [107] thiab yog li ntawd lipid hloov pauv yuav tsum tau ua kom haum rau txhua lub cev.

Lipids yog ib chav kawm tseem ceeb heev ntawm biomolecules uas ua lub luag haujlwm tseem ceeb hauv txhua yam ntawm peb lub neej. Ntxiv nrog rau lawv lub luag haujlwm tseem ceeb hauv cov txheej txheem ntawm cov cell membranes, lipids kuj tseem txuas nrog kev txhim kho kev nco.

Ua ntej, lipids yog ib qho ntawm cov khoom tseem ceeb ntawm lub paj hlwb. Peb lub paj hlwb thiab lub paj hlwb xav tau ntau cov lipids los tswj cov kev ua haujlwm lom neeg. Kev tshawb fawb yav dhau los tau pom tias cov ntsiab lus lipid muaj feem cuam tshuam nrog kev txhim kho ntawm lub hlwb kev txawj ntse, tshwj xeeb tshaj yog kev txhim kho kev nco.

Qhov thib ob, lipids ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv thiab kho cov hlwb hlwb. Ntau qhov kev tshawb fawb tau pom tias nyob rau hauv cov neeg laus, kev laus thiab kev puas tsuaj rau lub hlwb feem ntau ua rau kev nco poob. Kev noj cov zaub mov uas muaj lipid-nplua nuj los yog cov vitamins tuaj yeem pab tiv thaiv thiab kho peb lub hlwb, yog li txhim kho peb lub cim xeeb.

Zuag qhia tag nrho, lipids yog inextricably txuas rau kev nco. Peb yuav tsum tsis tu ncua noj cov zaub mov uas nplua nuj lipid thiab tswj kev noj qab haus huv thiab kev ua neej nyob hauv peb lub neej txhua hnub kom tswj tau peb txoj kev noj qab haus huv thiab kev nco. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Lipidcomposition cuam tshuam rau ntau yam khoom ntawm cov kab mob organelle, suav nrog nws cov curvature thiab cov proteins nrhiav tau rau ob lub ntsej muag cytoplasmic ntawm organelle thiab transmembraneproteins [108].

Lipids tau paub tias raug thauj los ntawm ER mus rau lwm cov organelles viavesicular thiab non-vesicular thauj mechanisms, xws li lipid hloov cov proteins. Lipid hloov ntawm ER mus rau Golgi apparatus tshwm sim los ntawm vesicular mechanism, uas yog ib feem ntawm txoj kev secretory, thiab Los ntawm monomolecular lipid thauj mediated los ntawm lipid hloov cov proteins ntawm ER-Golgi interface.

Nyob rau hauv txoj kev thauj vesicular, daim nyias nyias tawm ntawm ER ntawm ERES (Tshooj 2.2.2) thiab tib lub vesicles / tubular-vesicularclusters uas nqa ER-synthesised proteins los ntawm ER mus rau Golgi tuaj yeem muaj lipidsmetabolized hauv ER [109]. Cov lipids tom qab ntawd txuas ntxiv mus rau txoj hauv kev zais cia kom mus txog lawv qhov chaw.Lipid hloov pauv cov proteins khiav lipids ntawm organelles uas tsis txuas nrog txoj kev thauj mus los [83].

Cov hloov pauv cov protein no muaj txiaj ntsig zoo ntawm cov chaw sib txuas ntawm daim nyias nyias ntawm ER thiab plasma membrane [110–116], Golgi apparatus [117–119], thiab endosomes [120–125] (lipid hloov cov proteins ntawm ER MCSs tsis ntev los no tau tshuaj xyuas [108] ). Cov ntaub ntawv pov thawj tsis ntev los no tau raug tshawb pom rau peb-txoj kev MCSs ntawm ER, lig endosomes, thiab mitochondria, ntawm PDZD8, cov protein uas muaj cov lipid transferdomain thiab cuam tshuam nrog protrudin, cov khoom tseem ceeb rau ER motility (Section 3.1.2), thiab Rab7 [126]. Qhov kev sib cuag peb txoj kev no yog kev xav kom pab txhawb kev hloov lipid ntawm peb lub cev.

Kev sib cuag ntawm ER thiab lig endosomes / lysosomes koom nrog ER-anchored VAP cov proteins (piv txwv li, [82,127–129]), thiab cov kev sib cuam tshuam no yog rhiab rau cov khoom noj [128,129]. Qhov tseem ceeb, cov chaw sib cuag ntawm cov endosomes thaum ntxov thiab theER hauv cov roj cholesterol tsawg pab txhawb kev hloov cov roj cholesterol los ntawm ER mus rau lawv lub cev, qhov uas nws yuav tsum tau tsav endosomal sorting los ntawm kev tsim ntawm intraluminal vesicles (ILVs) [120].

Raws li ib sab, ER-thaum ntxov endosome tiv tauj kuj pab txhawb ILV tsim los ntawm kev muab cov chaw nyob qhov twg ER-localised protein tyrosine phosphatase1B dephosphorylates endocytosed, active kev loj hlob receptors xws li cov epidermalgrowth factor receptor, uas yuav tsum tau rau EGFR yuav tsum tau muab faib mus rau hauv ILVs. . Qhov no tej zaum yog vim li cas motile thaum ntxov endosomes tau pom kom nres ntawm ER tubules [74].

Kev hloov pauv cov roj cholesterol bidirectional kuj tshwm sim ntawm kev sib cuag ntawm ER thiab lig endosomes / lysosomes (saib hauv [86,131]), thiab cov chaw no koom nrog ntau cov proteins uas cuam tshuam rau hauv kev nrhiav neeg ua haujlwm microtubule motors (saib hauv qab).Peroxisomes thiab ER yuav tsum pauv lipids. Raws li cov synthesis ntawm qee cov lipids, piv txwv li, ether phospholipids, pib hauv peroxisomes tab sis ua tiav hauv ER [132,133].

Cov lipid hloov pauv protein VPS13D tau tshawb pom ntawm ob qho tib si ER-peroxisome, thiab ER-mitochondria hu, qhov twg nws cuam tshuam nrog Miro [134], thiab lwm yam, VPS13A, tau pom ntawm ER-mitochondria hu [124], thiab qhov kev thauj lipid no yog tseem ceeb rau peroxisome biogenesis [135]. Cov tshuab koom nrog hauv kev tsim ER-peroxisome MCSs tsis ntev los no tau tshawb pom [136] thiab muaj qee cov pov thawj rau cov tsis-vesicular ER rau peroxisome lipid thauj [137].

Ib yam li ntawd, phosphatidylserine yuav tsum tau hloov los ntawm ER, qhov chaw uas nws yog synthesized, mus rau mitochondria, qhov twg nws hloov mus rau phosphatidylserines [138-140]. Nws tau pom tias qhov kev hloov lipid no tshwm sim txawm tias tsis muaj cytosolic phospholipid pauv cov proteins lossis cov hlwv me me [139,140] thiab yog li yuav tshwm sim los ntawm lipid hloov cov proteins ntawm ER-mitochondria MCSs.ERMES (ER-mitochondria ntsib qauv), muaj protein ntau pom nyob rau hauv poov xab, tau raug npaj ua ib qho kev sib txuas ntawm ob lub organelles [141–144].

Cov complex no kuj tseem tuaj yeem hloov cov lipids ntawm qhov chaw sib cuag, los ntawm kev thauj cov protein xws li Lam6 / Ltc1. Lam6 cuam tshuam nrog mitochondrial proteins Tom70 thiab Tom71 ntawm ER-mitochondrial MCSsand paub tias hloov cov sterols hauv vitro [145–147]. Ib yam li ntawd, PDZD8 tuaj yeem ua tiav lub luag haujlwm zoo sib xws [126].Cov kev tsis yog vesicular no yog ib qho tseem ceeb ntawm kev lag luam lipid.

Tseeb, nws tau pom tias tus nqi ntawm lipid hloov ntawm ER mus rau plasma daim nyias nyias tsis pom zoo txo ​​qis thaum txoj kev vesicular raug thaiv [148-151], qhia tias tsis yog-vesicular thauj ib leeg tuaj yeem txhawb nqa qhov xav tau lipid hloov mus rau plasma membrane.

Raws li MCSs ntawm ER thiab lwm yam organelles, tshwj xeeb tshaj yog cov plasma daim nyias nyias, mitochondria, thiab endosomes [73-78], nyiam tsim nyob rau hauv tubular ER network, cov kev tshawb pom no qhia tias kev hloov pauv lipid tshwm sim feem ntau hauv tubular ER.

2.2.5. MCSs: Calcium Control

Lwm qhov tseem ceeb ntawm ER yog calcium ion sequestration thiab tso tawm. Ca2+ yog ib qho tseem ceeb taw qhia molecule, qhov concentration ntawm uas cuam tshuam tsis tsuas yog lub luag haujlwm ntawm ER tab sis kuj muaj ntau yam ntawm lwm txoj hauv kev, suav nrog mitochondrial metabolism thiab apoptosis [152–154].

Chaperone proteins nyob rau hauv ER xws li calnexin [155], calreticulin [156], thiab protein disulfide isomerase [157], thiab lwm yam, khi rau Ca2+ thiab lawv ua hauj lwm raws li chaperones nyob rau hauv protein folding yog nyob ntawm cov calcium ion concentration. hauv ER [158,159]. Kev sib sau ntawm cov khoom noj tsis raug cai ua rau ER kev ntxhov siab thiab ua rau cov lus teb tsis muaj protein ntau (UPR), uas tuaj yeem kho ER homeostasis orinduce apoptosis, nyob ntawm seb cov xwm txheej ntawm tes (saib hauv [160]). Yog li, kev tswj hwm ntawm Ca2+ concentration yog qhov tseem ceeb rau kev ua haujlwm ntawm tes.

Calcium ions raug tso tawm los ntawm ER los ntawm transmembrane receptors, feem ntau theryanodine receptor (RyR) thiab inositol 1,4, 5-trisphosphate receptor (IP3R), nyob rau hauv kev teb rau intracellular cues.

Mitochondria nyob rau hauv txoj haujlwm ze rau IP3Rs [161,162] coj Ca2+ ions thaum lawv tso tawm. Calcium ions yog tsim nyog rau mitochondrialmetabolism, suav nrog ATP ntau lawm thiab txo cov pyridine nucleotides [152,153].Rau hloov Ca2+, ib qho nyuaj yog tsim los ntawm ER-neeg nyob IP3R thiab voltage-dependent anion channel 1 (VDAC1) nyob rau hauv lub sab nrauv mitochondrial membrane [161,163,164].Grp75, ib tug cytosolic protein, tsim ib tug tether ntawm cov channel los pab Ca{16}} hloov mus rau mitochondria [165].

Mitofusin 2 kuj tseem cuam tshuam rau ob qho tib si ER-mitochondrial tethering thiab mitochondrial calcium uptake [105], txawm hais tias muaj qee qhov kev sib cav txog nws lub luag haujlwm (saib hauv [166]). MCSs ntawm ER thiab mitochondria, uas feem ntau tshwm sim hauv tubular ER, yog qhov tseem ceeb heev rau calcium ion homeostasis [85]. IP3Rs kuj tseem cuam tshuam cov calcium hloov mus rau lysosomes ntawm ER-lysosome MCSs [167].

Raws li ER calcium ion depletion, kev nkag mus ntawm Ca2+ los ntawm cov khoom siv hluav taws xob ntxiv yog yuav tsum tau ua kom cov lumenal Ca2+ concentration. Kev thauj mus los ntawm Ca2+ mus rau hauv lub cell yog ua tiav los ntawm kev koom tes ntawm STIM1 thiab Orai1.

Tom qab cov khw muag khoom calcium tau tas lawm, ERResident protein STIM1 [168] thiab cov plasma membrane calcium channel, Orai1 [169], raug xa mus rau ER-PM MCSs [170] qhov chaw lawv tsim ib qho nyuaj [171]. Orai1 yog calcium tso tawm-activated calcium (CRAC) channel uas qhib thaum muaj kev cuam tshuam nrog STIM1 tshwm sim [172]. Cov txheej txheem ntawm Ca{11}} influx no hu ua khw-ua haujlwm calcium nkag (SOCE).

Lub Ca2+ nkag mus rau hauv lub cell yog thauj mus rau hauv ER ntawm sarco/endoplasmic-reticulumCa2+ ATPase (SERCA) twj. Cov twj no siv ATP los thauj cov calcium ions tawm tsam Ca2+ concentration gradient rau hauv ER, refilling lumenal calcium stores [173–175].

Los ntawm kev ua haujlwm tau piav qhia ntawm no, nws pom tseeb tias MCSs nrog mitochondria thiab cov ntshav cov ntshav yog lub luag haujlwm rau calcium ion tso tawm los ntawm ER thiab nkag mus los ntawm thaj av sab nraud raws li. STIM1 tseem ua lub luag haujlwm tseem ceeb hauv ER dynamics, los ntawm kev sib txuas ER tubules kom loj hlob microtubules los tsim cov tip attachment complexes (TACs), raws li tau piav qhia hauv Tshooj 3.1.3.

2.2.6. MCSs: Tswj Membrane Fission thiab Fusion

Ib qho kev ntxim nyiam ntawm MCS muaj nuj nqi yog tias nyob rau hauv ob peb kis, lawv ua raws li cov hotspots formembrane fission los yog fusion ntawm organelle khi rau ER. Piv txwv li, mitochondrialfission tshwm sim ntawm cov ntsiab lus uas lawv hu rau ER tubules thiab ua rau constricted ua ntej fission protein Drp1 yog enriched [38,73].

Drp1 yeej ib txwm sau ntawm, lossis ib sab ntawm, ER-ER-mitochondrial hu. Interestingly, Drp1 tsis ntev los no tau pom tias yuav pab txhawb ERtubule tsim thiab nyob rau hauv tag nrho cov ER tubules nyob rau theem qis, nrog rau cov generatingsites rau mitochondrial-ER kev sib cuam tshuam thiab mitochondrial fission [42]. Txawm li cas los xij, lub luag haujlwm no ingenerating ER tubules tsis tas yuav Drp10s GTPase kev ua, uas yog qhov tseem ceeb rau mitochondrial fission [42].

Mitochondrial fusion kuj tau pom tias tshwm sim ntau zaus thaum mitochondria txuas nrog ER [38].Raws li tau hais los saum toj no, ER kuj tsim kev sib cuag nrog cov endosomes thaum ntxov, thiab cov kwj dej no kuj yog qhov chaw ntawm endosome fission [176].

Ib qho isoform ntawm microtubule-severing proteinspastin localizes ntawm ER daim nyias nyias, thiab nws cuam tshuam nrog thaum ntxov endosomal ESCRTprotein IST1 ntawm ER-thaum endosome hu los tsav endosomal tubule fission thiab sorting.Disrupting no kev sib cuam tshuam coj mus rau lub misorting ntawm lysosomal enzymes alsofect thiab uas zoo li yuav yog vim li cas vim li cas spastin mutations ua rau hereditary spastic paraplegia [177].

Lwm cov ER protein, reticulon 3L, tsis ntev los no tau pom tias yuav raug xaiv mus rau ER-endosome cov chaw sib cuag los ntawm Rab9 thiab txhawb endosome maturation thiab sorting [178], yuav piav qhia vim li cas endosome maturation correlates nrog enhanced interactions nrog ER [75]. Nws yuav nthuav kom txiav txim siab seb cov no puas yog tib txoj kev sib txawv.

Ntau tshaj 90% ntawm lig endosomes / lysosomes yog txuam nrog ER [38,179] thiab 80% ntawm endosomal fission tshwm sim thaum txuam nrog ER [176]. Retromerdrives sorting thiab recycling ntawm cov khoom los ntawm lig endosome mus rau lub Golgi apparatus, thiab cov scission ntawm retromer tubules tshwm sim ntawm cov ntsiab lus ntawm kev sib cuag nrog ER thiab xav tau ER membrane protein, TMCC1 uas accumulates ntawm ER-endosome tiv tauj qhov chaw, theactin-binding protein. coronin 1 [179], thiab WASH complex [127] thiab nws interactor, strumpelin [177].

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