劉靜，易聰，許師明

蛋白質(zhì)乙?；揎棇?duì)自噬的調(diào)控作用

劉靜，易聰，許師明

浙江大學(xué)醫(yī)學(xué)院，杭州 310020

自噬是一種依賴于液泡或溶酶體，從酵母到人類都高度保守的物質(zhì)降解途徑，其在維持細(xì)胞穩(wěn)態(tài)過程中起重要作用。自噬功能的異常與人類多種重大疾病如神經(jīng)退行性疾病、代謝性疾病及惡性腫瘤的發(fā)生發(fā)展密切相關(guān)。作為維持生物體內(nèi)穩(wěn)態(tài)平衡的重要生物學(xué)過程，細(xì)胞自噬的發(fā)生受到精密的調(diào)控。乙?；揎椬鳛橐环N可逆的蛋白翻譯后修飾(post-translational modification, PTM)，在自噬的精密調(diào)控中發(fā)揮重要作用。本文主要對(duì)近年來乙?；揎椩谧允烧{(diào)控中的相關(guān)研究進(jìn)行了綜述，以期為自噬領(lǐng)域的基礎(chǔ)研究提供思路，同時(shí)也為研究人員探索自噬相關(guān)疾病的預(yù)防和治療方法提供參考。

自噬；乙酰化；自噬相關(guān)蛋白

細(xì)胞在應(yīng)對(duì)不同壓力刺激(如血清饑餓、氨基酸饑餓、葡萄糖饑餓或雷帕霉素處理)時(shí)會(huì)誘導(dǎo)大量自噬發(fā)生以降解自身物質(zhì)用于維持細(xì)胞穩(wěn)態(tài)。這些被自噬途徑降解的物質(zhì)包括生物大分子(如蛋白質(zhì)、脂質(zhì)、糖類及核酸)及整個(gè)受損的細(xì)胞器等。自噬是生物體進(jìn)化過程中高度保守的分解代謝途徑，酵母中發(fā)現(xiàn)的自噬基因在哺乳動(dòng)物細(xì)胞中絕大部分能夠找到其同源物。目前已經(jīng)在酵母細(xì)胞中鑒定出40多種自噬相關(guān)基因(autophagy-related genes,)，這些基因編碼的蛋白質(zhì)使得細(xì)胞在面對(duì)內(nèi)外壓力刺激時(shí)，通過啟動(dòng)細(xì)胞自噬來適應(yīng)環(huán)境改變[1,2]。蛋白質(zhì)的翻譯后修飾(post-translational modification, PTM)則在細(xì)胞自噬的快速應(yīng)答過程中扮演重要作用[3,4]。

早在20世紀(jì)60年代，PTM已被證明在調(diào)控細(xì)胞生理功能方面起重要作用[5,6]。在21世紀(jì)初期，得益于高分辨率質(zhì)譜的應(yīng)用，對(duì)于PTM的研究也取得了長足的進(jìn)步[7]。PTM通過對(duì)蛋白質(zhì)的不同化學(xué)修飾而具有不同的生物功能，極大地?cái)U(kuò)展了真核生物蛋白功能調(diào)控的多樣性。目前已發(fā)現(xiàn)蛋白質(zhì)存在多種翻譯后修飾參與細(xì)胞自噬的調(diào)控，如磷酸化、泛素化、蘇木化及乙酰化[8,9]。大量研究表明，乙?；诩?xì)胞自噬調(diào)控方面起重要作用，細(xì)胞中存在多種組蛋白乙?；?去乙酰化酶(histone acetyltrans-ferase/deacetylase, HAT/HDAC)參與自噬相關(guān)蛋白的乙酰化/去乙?；揎梉10]。本文主要關(guān)注蛋白乙酰化修飾調(diào)控細(xì)胞自噬的機(jī)制以及乙?；{(diào)控的自噬在相關(guān)疾病發(fā)生發(fā)展中的作用，以期為自噬基礎(chǔ)研究和相關(guān)疾病預(yù)防、治療提供思路。

1 自噬的概念

自噬是細(xì)胞內(nèi)一類依賴于溶酶體(酵母和植物為液泡)的物質(zhì)降解途徑，其降解底物包括如蛋白質(zhì)、聚集體、受損的細(xì)胞器等。作為細(xì)胞內(nèi)的分解代謝途徑，正常情況下自噬發(fā)生的水平較低，而在外界壓力刺激情況下，如饑餓、細(xì)胞器受損或低氧，細(xì)胞自噬能夠被大量誘導(dǎo)，使得細(xì)胞能夠快速、有效地應(yīng)對(duì)環(huán)境變化[11,12]。在真核細(xì)胞中，存在3種主要類型的自噬：微自噬(microautophagy)、巨自噬(macroautophagy)和分子伴侶介導(dǎo)的自噬(chaperone- mediated autophagy, CMA)。微自噬是指真核細(xì)胞通過溶酶體內(nèi)陷并包裹胞質(zhì)內(nèi)部分物質(zhì)進(jìn)入溶酶體進(jìn)行降解；巨自噬則是通過將細(xì)胞質(zhì)中需要被降解的物質(zhì)包裹進(jìn)入一類雙層膜結(jié)構(gòu)形成自噬體，隨后自噬體與溶酶體融合成為自噬溶酶體，利用溶酶體中的酸性水解酶將自噬體內(nèi)的物質(zhì)進(jìn)行降解；分子伴侶介導(dǎo)的自噬通過熱休克蛋白70 (heat-shock cognate protein 70, HSC70)和帶特定氨基酸序列的底物結(jié)合并將底物轉(zhuǎn)運(yùn)至溶酶體進(jìn)行降解[13～15]。

2 蛋白質(zhì)乙酰化修飾

乙?；揎?acetylation)是指在乙?；傅淖饔孟聦⒁阴］o酶A的乙?；鶊F(tuán)轉(zhuǎn)移至蛋白質(zhì)氨基酸殘基上。目前研究最多的乙?；揎検墙M蛋白上的乙?；揎?，其在表觀調(diào)控過程中發(fā)揮重要作用。然而，乙?；揎椀墓δ懿⒉幌拗朴诮M蛋白，在胞質(zhì)及其他亞細(xì)胞器中的蛋白也存在著非常豐富的乙?；揎?，這些發(fā)生在非組蛋白上的乙?；揎棻环Q為非組蛋白乙?；揎梉16]。

從分類上說，乙?；揎椫饕譃閮深悾喊l(fā)生在蛋白N端的乙酰化修飾，以及發(fā)生在蛋白賴氨酸上的乙酰化修飾。前者發(fā)生在90%以上的真核生物新生蛋白上，對(duì)于新生蛋白的成熟和細(xì)胞定位非常重要，由N乙酰轉(zhuǎn)移酶(N acetyltransferase, NAT)負(fù)責(zé)；而后者是一個(gè)可逆的過程，主要由賴氨酸乙酰化酶(lysine(K) acetyltransferase, KAT)和賴氨酸去乙?；?lysine deacetylase, KDAC)負(fù)責(zé)[17]。賴氨酸的乙?；揎検潜疚奶接懙闹攸c(diǎn)，如無特殊說明，下文中提到的乙?；鶠橘嚢彼岬囊阴；揎?。

賴氨酸乙?；羌?xì)胞內(nèi)蛋白的一種可逆翻譯后修飾，由美國科學(xué)家Vincent Allfrey于1964年首次在組蛋白中發(fā)現(xiàn)，是存在于真核生物中進(jìn)化上保守的翻譯后修飾形式[9]。催化乙?；D(zhuǎn)移到組蛋白賴氨酸殘基上的酶被稱為賴氨酸乙酰化酶，通常稱為組蛋白乙酰化酶，此過程還需要乙酰輔酶A和ATP的參與。在蛋白乙?；揎椷^程中，乙?；笇⒁阴］o酶A上的乙?；D(zhuǎn)移到底物蛋白的賴氨酸氨基側(cè)鏈上。近年來，這些乙?；副话l(fā)現(xiàn)還可以乙?；幌盗蟹墙M蛋白，包括p53、Rb和MYC等[10]。相應(yīng)的HDAC則是負(fù)責(zé)將蛋白殘基上的乙?；コＱ芯勘砻?，HAT和HDAC可快速地進(jìn)行蛋白的乙?；揎椏刂?，從而調(diào)控基因的轉(zhuǎn)錄和蛋白活性，參與生物體的多種生理功能[18]。

3 組蛋白乙?；揎椗c自噬調(diào)控

組蛋白是染色質(zhì)核小體的組成成分之一，H1、H2A、H2B、H3和H4 5種組蛋白(histone, H)與DNA共同構(gòu)成染色質(zhì)的結(jié)構(gòu)單元—核小體。與其他蛋白一樣，組蛋白活性也受PTM調(diào)控，組蛋白PTM主要包括磷酸化、泛素化、甲基化和乙?；＝M蛋白乙?；且环N主要發(fā)生在H3和H4組蛋白N端的一種保守的賴氨酸殘基修飾，受HAT和HDAC的協(xié)調(diào)調(diào)控[19]。目前研究認(rèn)為，HAT將乙酰基添加到組蛋白N末端賴氨酸的氨基上，通過它們介導(dǎo)染色質(zhì)的去凝集，促進(jìn)基因的轉(zhuǎn)錄。HDAC則可將乙?；鶑慕M蛋白上去除并誘導(dǎo)組蛋白與DNA的緊密結(jié)合[20,21]。

2004年，Shao等[22]發(fā)現(xiàn)HDAC抑制劑丁酸和辛二酰苯胺異羥肟酸(suberoylanilide hydroxamic acid β-D-glucuronide, SAHA)可以誘導(dǎo)癌細(xì)胞發(fā)生自噬式死亡。該研究結(jié)果使得人們關(guān)注到了非組蛋白乙?；瘜?duì)于自噬的調(diào)控作用。Eisenberg等[23]則是第一個(gè)將自噬活性與組蛋白乙?；揎楆P(guān)聯(lián)起來，在老化的酵母中，他們確定亞精胺對(duì)細(xì)胞自噬的誘導(dǎo)依賴于其對(duì)HAT活性的抑制，亞精胺會(huì)導(dǎo)致組蛋白H3的整體乙?；浇档?，因此可能反映某類基因表達(dá)受到抑制。

組蛋白乙?；趹?yīng)對(duì)長期營養(yǎng)缺乏或壓力刺激情況下誘導(dǎo)自噬發(fā)生發(fā)揮重要作用。研究最多的是H4第16位賴氨酸(H4K16ac)和H3第56位賴氨酸(H3K56ac)乙?；c自噬活性的關(guān)系[24]。在哺乳動(dòng)物細(xì)胞中，H4K16ac影響染色質(zhì)凝集狀態(tài)，促進(jìn)相關(guān)基因的轉(zhuǎn)錄表達(dá)。研究表明，乙?；?KAT8/hMOF/ MYST1為H4K16乙?；匦璧摹＿M(jìn)一步研究發(fā)現(xiàn)，KAT8和SIRT1是調(diào)控H4K16乙?；降囊粚?duì)分子開關(guān)，并由此來調(diào)節(jié)細(xì)胞中的自噬活性[25]。H4K16去乙?；c自噬相關(guān)基因的表達(dá)下調(diào)直接相關(guān)，例如自噬相關(guān)基因和等[26]。組蛋白H3-H4酵母突變體文庫鑒定結(jié)果表明，TOR抑制劑雷帕霉素處理細(xì)胞導(dǎo)致H3K56ac減少[27]。此外，在人體中，組蛋白乙?；窫P300/KAT3B/ p300和KAT2A/GCN5都負(fù)責(zé)H3K56的乙?；秸{(diào)控[28]。p300的敲低可以誘導(dǎo)細(xì)胞自噬，而p300的過表達(dá)則抑制饑餓誘導(dǎo)的自噬的發(fā)生[29]。

4 非組蛋白乙酰化與細(xì)胞自噬

非組蛋白也可以被乙?；揎棧瑓⑴c細(xì)胞自噬的調(diào)控。這些蛋白涉及到轉(zhuǎn)錄因子、自噬相關(guān)的蛋白及細(xì)胞骨架蛋白等。

4.1 轉(zhuǎn)錄因子

4.1.1 FoxO蛋白

FoxO蛋白家族(FoxO1、FoxO3、FoxO4和FoxO6)主要作為轉(zhuǎn)錄激活劑發(fā)揮作用，它們的活性除了受到胰島素和生長因子信號(hào)抑制外，乙?；揎椧部梢杂绊懫浠钚訹30]。FoxO蛋白上的賴氨酸殘基能夠被HAT如 p300、CREB結(jié)合蛋白(CBP)和CBP相關(guān)因子等乙酰化，乙?；腇oxO活性出現(xiàn)降低，進(jìn)而抑制FoxO蛋白與DNA的結(jié)合[31]。此外，NAD依賴性的去乙?；竤irtuin-1(SIRT1)也可以通過調(diào)節(jié)FoxO活性影響細(xì)胞自噬，SIRT1去乙?；⒓せ頕oxO3，活化的FoxO3在骨骼肌中結(jié)合并激活參與自噬體形成的基因，包括和的表達(dá)[32]。在血清饑餓或氧化應(yīng)激下，細(xì)胞質(zhì)FoxO1的乙?；扇ヒ阴；窼IRT2的解離誘導(dǎo)，乙?；疐oxO1結(jié)合并激活A(yù)TG7以增強(qiáng)自噬[33]。

4.1.2 TFEB蛋白家族

TFEB蛋白作為轉(zhuǎn)錄因子能夠調(diào)控自噬相關(guān)基因，如、和等的轉(zhuǎn)錄，在溶酶體生物合成和自噬的激活過程中起重要作用[34]。作為MiT/TFE轉(zhuǎn)錄因子家族的一員，TFEB 的活性主要受雷帕霉素靶標(biāo)(mTOR)的調(diào)控，它決定了TFEB的亞細(xì)胞定位[35]。有趣的是，研究發(fā)現(xiàn)TFEB的轉(zhuǎn)錄因子活性也受其乙酰化修飾的調(diào)控，TFEB的去乙酰化能夠顯著提高細(xì)胞的自噬及溶酶體功能[36]。乙酰輔酶A乙酰化酶1 (Acetyl-CoA acetylase 1, ACAT1) 和組蛋白去乙?；窼IRT1及HDAC2會(huì)影響TFEB的乙酰化水平[36,37]。此外，Wang等[38]鑒定出TFEB特異性的賴氨酸乙酰化酶GCN5，GCN5可通過乙酰化TEFB的K276和K279位點(diǎn)干擾TFEB二聚化的形成以及隨后TFEB與其靶基因啟動(dòng)子上結(jié)合位點(diǎn)的結(jié)合，從而抑制自噬的發(fā)生。

表1 自噬相關(guān)蛋白(ATG)的乙酰化對(duì)于自噬的調(diào)控

4.2 自噬相關(guān)蛋白

除了組蛋白和轉(zhuǎn)錄因子外，還有許多自噬相關(guān)蛋白通過乙酰化/去乙?；揎椪{(diào)控細(xì)胞自噬(表1)。

4.2.1 LC3

微管相關(guān)蛋白1輕鏈3 (microtubule-associated protein 1 light chain 3, LC3，酵母ATG8同源物)是自噬的關(guān)鍵調(diào)節(jié)因子，在自噬體膜的形成過程中，胞質(zhì)LC3 (LC3-I)通過由泛素活化酶E1樣酶ATG7和泛素結(jié)合酶E2樣酶ATG3生成LC3-II[53,54]。在自噬體與溶酶體融合期間，自噬體內(nèi)的LC3-II也被溶酶體內(nèi)的酸性水解酶所降解[55,56]。作為自噬體膜的標(biāo)志物，細(xì)胞LC3-II水平的變化與LC3-II通過溶酶體的動(dòng)態(tài)周轉(zhuǎn)有關(guān)，因此LC3-II被作為哺乳動(dòng)物自噬發(fā)生的標(biāo)志物廣泛使用[57]。研究表明，在自噬體形成過程中，LC3的去乙酰化導(dǎo)致的LC3出核是啟動(dòng)細(xì)胞自噬發(fā)生的必要條件[58]。在富營養(yǎng)情況下，乙?；竝300乙酰化修飾LC3，乙?；腖C3主要分布在細(xì)胞核內(nèi)，導(dǎo)致LC3無法啟動(dòng)自噬[43,59]。乙?；€抑制了LC3通過蛋白酶體依賴途徑降解[43]。在營養(yǎng)匱乏(如血清剝奪或葡萄糖饑餓)條件下，細(xì)胞核內(nèi)的LC3由去乙酰化酶SIRT1去乙?；⑴c糖尿病和肥胖調(diào)節(jié)的核因子(diabetes- and obesity-regula-ted nuclear factor, DOR)結(jié)合，轉(zhuǎn)位到細(xì)胞質(zhì)與 ATG7、p62等自噬相關(guān)蛋白結(jié)合形成復(fù)合體，啟動(dòng)細(xì)胞自噬[42,43,60]。

4.2.2 VPS34

VPS34是哺乳動(dòng)物中唯一的III類磷酸肌醇3-激酶(PI3K)，可將磷脂酰肌醇(PtdIns, PI)磷酸化產(chǎn)生 3-磷酸磷脂酰肌醇(PI3P)，細(xì)胞PI3P的產(chǎn)生與自噬前體的形成密切相關(guān)[61～63]。Russell等[64,65]發(fā)現(xiàn)氨基酸饑餓會(huì)使mTORC1失活，無法磷酸化ULK1的S757位點(diǎn)，進(jìn)而激活ULK1，激活的ULK1進(jìn)一步與ATG14L結(jié)合并磷酸化Beclin 1，導(dǎo)致新生自噬體中的VPS34激酶激活并產(chǎn)生PI3P。Su等[44]最近揭示了一種新的PIK3C3/VPS34激活調(diào)節(jié)機(jī)制：在營養(yǎng)豐富條件下，細(xì)胞VPS34的活性被p300介導(dǎo)的乙酰化抑制。同時(shí)，p300作為乙酰化轉(zhuǎn)移酶的活性受mTORC1活性的調(diào)控。在正常情況下，細(xì)胞內(nèi)的mTORC1處于活化狀態(tài)，p300被mTORC1磷酸化，致使p300活化，使細(xì)胞內(nèi)乙?；疞C3升高，阻礙LC3與ATG7的結(jié)合，從而抑制細(xì)胞自噬發(fā)生[42,43,66]。而在營養(yǎng)匱乏時(shí)，mTORC1失活導(dǎo)致p300活性下降后，VPS34通過去乙酰化作用被釋放。進(jìn)一步的研究發(fā)現(xiàn)，p300依賴的乙酰化和去乙?；顷P(guān)閉/打開VPS34的激酶活性的開關(guān)，N端K29殘基的去乙?；呛诵膹?fù)合物形成的原因，而C端K771位點(diǎn)的去乙?；荲PS34完全激活所必需，該位點(diǎn)的去乙?；瘺Q定了VPS34與其底物PI的結(jié)合[44]。這種VPS34激活機(jī)制不僅在饑餓誘導(dǎo)的自噬過程中起重要作用，而且對(duì)于AMPK、mTORC1或ULK1-非依賴性的非經(jīng)典自噬的發(fā)生也非常重要[44]。

4.2.3 其他自噬相關(guān)蛋白

ATG 蛋白是細(xì)胞自噬發(fā)生的重要調(diào)控蛋白，研究發(fā)現(xiàn)許多ATG蛋白能夠被乙?；揎?。ULK1 (酵母ATG1的同源物)是自噬的關(guān)鍵調(diào)控因子，AMPK和mTORC1這兩個(gè)激酶都可催化ULK1的磷酸化，這在自噬啟動(dòng)過程中起重要作用[67]。Lin等[45]發(fā)現(xiàn)高等動(dòng)物細(xì)胞在生長因子缺失條件下，糖原合酶激酶3 (glycogen synthase kinase-3, GSK3)能激活乙?；窽IP60，從而乙?；鞍准っ窾LK1，啟動(dòng)細(xì)胞自噬。ATG5、ATG7和ATG12是形成自噬體所必需的自噬核心蛋白，它們均可以被乙酰化酶p300乙?；．?dāng)營養(yǎng)豐富時(shí)，p300與這些ATG蛋白相互作用[29,39]；當(dāng)細(xì)胞處于饑餓狀態(tài)時(shí)，sirtuins被激活，SIRT1與ATG5、ATG7和LC3形成復(fù)合物，導(dǎo)致這些ATG蛋白去乙?；瑥亩T導(dǎo)細(xì)胞自噬發(fā)生[46,60,68]，同時(shí)，基因敲除小鼠顯示這些蛋白的基礎(chǔ)乙?；黾?，并且在饑餓時(shí)無法完全激活自噬，進(jìn)一步支持SIRT1是這些ATG蛋白的去乙酰酶[68]。在酵母細(xì)胞中，自噬蛋白ATG3能夠被乙?；窫sa1乙?；揎棧阴；腁TG3通過增強(qiáng)ATG3和ATG8的相互作用以及ATG8的脂化來啟動(dòng)細(xì)胞自噬發(fā)生[49,50]。Pacer作為脊椎動(dòng)物特異性的自噬調(diào)控蛋白，營養(yǎng)匱乏(血清剝奪)時(shí)，GSK3-TIP60信號(hào)介導(dǎo)的Pacer乙酰化修飾有利于Pacer與HOPS復(fù)合物及STX17 (syntaxin 17)的結(jié)合，促進(jìn)自噬體成熟[51,69]。作為調(diào)控自噬體成熟的SNARE蛋白，STX17對(duì)于自噬的調(diào)控也受其乙酰化影響，在細(xì)胞處于饑餓狀態(tài)下，乙酰化酶CREBBP失活導(dǎo)致STX17去乙?；?，進(jìn)而促進(jìn)STX17-SNAP29-VAMP8 SNARE復(fù)合物的形成；同時(shí)，STX17的去乙?；€增強(qiáng)STX17與HOPS復(fù)合物之間的相互作用，從而進(jìn)一步促進(jìn)自噬體成熟[52,70]。

5 乙?；{(diào)控的自噬與疾病

自噬是一種進(jìn)化保守的分解代謝過程，在多種疾病中發(fā)揮著極其重要的作用。自噬蛋白ATG16L的突變與克羅恩病(Crohn’s disease)的發(fā)生相關(guān)[71]。心肌細(xì)胞特異性基因缺失小鼠出現(xiàn)心臟肥大、左心室擴(kuò)張、收縮功能障礙和過早死亡[72,73]。在神經(jīng)退行性疾病中，tau蛋白和突觸核蛋白的積累往往歸因于細(xì)胞自噬降解蛋白質(zhì)能力下降[74,75]。大腦特異性基因缺陷小鼠的皮質(zhì)和小腦神經(jīng)元受到嚴(yán)重?fù)p傷，表現(xiàn)出抱肢反射和運(yùn)動(dòng)缺陷等異常的表型，與某些神經(jīng)退行性疾病的異常表型一致[76]。

蛋白乙?；揎椬鳛檎{(diào)控自噬發(fā)生的重要步驟，在疾病的發(fā)生發(fā)展過程中扮演重要角色。高脂飲食小鼠肝臟的Pacer蛋白乙?；浇档停琍acer蛋白乙?；降慕档蛣t導(dǎo)致自噬活性降低，最終導(dǎo)致肝臟脂質(zhì)代謝異常[51]。膠質(zhì)母細(xì)胞瘤(glioblastoma, GBM)患者病灶組織中的ATG5(T101)的磷酸化受缺氧誘導(dǎo)自噬調(diào)節(jié)因子PAK1 (p21 [RAC1] activated kinase 1)乙?；揎椀恼蛘{(diào)控，在缺氧誘導(dǎo)的自噬啟動(dòng)和維持GBM生長中起著重要作用[77]。微管蛋白乙酰化在神經(jīng)退行性疾病患者的腦部組織中普遍降低，這導(dǎo)致微管結(jié)構(gòu)解聚，損害微管依賴性運(yùn)輸，阻礙自噬體與溶酶體的融合，不利于錯(cuò)誤折疊蛋白的運(yùn)輸和清除[78,79]。去乙?；敢种苿?HDAC inhabitors, HDACi)，如SAHA、丙戊酸(valproic acid)、羅米地辛(romidepsin)等通過對(duì)細(xì)胞自噬的調(diào)控，展現(xiàn)出治療疾病的潛能[80]。曲古抑菌素A (trichostatin A, TSA)作為常用的去乙?；敢种苿芟∈笾鲃?dòng)脈弓縮窄(transverse aortic constriction, TAC)誘導(dǎo)的心臟組織的自噬反應(yīng)，使LC3-II水平正?；徑庋獕贺?fù)荷引起的心肌肥厚[81]。SAHA 是處于臨床試驗(yàn)階段的癌癥治療用去乙?；敢种苿渫ㄟ^下調(diào)AKT-mTOR信號(hào)傳導(dǎo)觸發(fā)自噬，將LC3-II募集到自噬體，增加細(xì)胞內(nèi)自噬溶酶體的形成，減緩小鼠移植腫瘤的生長[82]。這些研究結(jié)果提示，蛋白乙酰化修飾對(duì)自噬的調(diào)控在預(yù)防和治療相關(guān)疾病方面具有廣闊的應(yīng)用前景。

圖1 自噬相關(guān)蛋白的乙酰化參與自噬體的形成

細(xì)胞受到外界環(huán)境刺激，一方面導(dǎo)致細(xì)胞內(nèi)的 mTOR 失活使乙酰化酶 p300 磷酸化水平降低，p300 活性被抑制，導(dǎo)致VPS34 乙酰化水平降低，促進(jìn) VPS34-Beclin 1 自噬核心復(fù)合物的形成；另一方面，細(xì)胞的AMPK 激活并活化ULK1，活化的ULK1進(jìn)而磷酸化 Beclin 1，促進(jìn) PI3K 復(fù)合體的形成。同時(shí)，細(xì)胞核內(nèi)的組蛋白去乙?；?SIRT1 被活化導(dǎo)致LC3去乙?；?。去乙酰化的 LC3 與 DOR 結(jié)合并轉(zhuǎn)位到胞質(zhì)，參與自噬復(fù)合體的形成，最后這些復(fù)合體經(jīng)過逐步組裝形成自噬體。

6 結(jié)語與展望

乙酰化修飾幾乎參與了細(xì)胞自噬發(fā)生的每一個(gè)重要過程，組蛋白和轉(zhuǎn)錄因子的乙?；揎椪{(diào)控自噬相關(guān)基因的表達(dá)水平，乙?；?去乙酰化修飾調(diào)控自噬相關(guān)蛋白活性，對(duì)細(xì)胞自噬進(jìn)行迅速、精準(zhǔn)地調(diào)控，有助于細(xì)胞穩(wěn)態(tài)維持。由此可見蛋白乙?；揎椩谧允苫虻霓D(zhuǎn)錄，自噬的啟動(dòng)、延伸和融合等多個(gè)層次均扮演著重要角色(圖1)。

作為高度靈活的開關(guān)，PTM 除了調(diào)控蛋白活性和細(xì)胞定位外，PTM之間的相互作用也參與細(xì)胞信號(hào)傳導(dǎo)的調(diào)節(jié)，這一過程被稱為PTM交互應(yīng)答(cross-talk)[83]。同一蛋白質(zhì)分子上可能存在多種PTM協(xié)同作用來決定其功能，如轉(zhuǎn)錄因子MEF2D絲氨酸S444磷酸化是后續(xù)K439發(fā)生蘇木化所必需[84]。研究人員鑒定出466個(gè)同時(shí)經(jīng)泛素化和磷酸化修飾的蛋白，并且磷酸化位點(diǎn)可利用泛素–蛋白酶體系統(tǒng)調(diào)控蛋白的降解[85]。GSK3β-TIP60-ULK1和mTORC1- p300-VPS34等通路均是通過乙?；c其他PTM之間的連鎖反應(yīng)參與細(xì)胞自噬的調(diào)控[44,45]。蛋白乙?；揎検且粋€(gè)動(dòng)態(tài)變化的過程，并且不同的PTM之間存在交互應(yīng)答，這可能使得PTM形成一個(gè)獨(dú)特的網(wǎng)絡(luò)[86]。未來乙酰化修飾參與自噬調(diào)控的研究應(yīng)該集中在乙?；c其他PTM之間的交互應(yīng)答網(wǎng)絡(luò)以及它們對(duì)自噬活性的影響，將各種PTM修飾整合到一個(gè)動(dòng)態(tài)網(wǎng)絡(luò)中，為阿爾茨海默病、帕金森病和癌癥等相關(guān)疾病提供理論基礎(chǔ)及可能的治療靶點(diǎn)。

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The regulatory effect of protein acetylation modification on autophagy

Jing Liu, Cong Yi, Shiming Xu

Autophagy is a highly conserved material degradation pathway from yeast to humans that depends on vacuoles or lysosomes. It plays an important role in the maintenance of homeostasis, and its dysfunction is closely related to the pathogenesis of major diseases, such as neurodegenerative disorders, metabolic diseases, and malignant tumors. As an important biological process for the maintenance of homeostasis, autophagy is highly regulated. Acetylation of proteins is a reversible post-translational modification and plays an important role in the regulation of autophagy. In this review, we summarize research results on the modulation of acetylation in the regulation of autophagy and aim to provide insights into this biological process for the advancement of the basic research and development of preventive and therapeutic strategies against autophagy-related diseases.

autophagy; acetylation; autophagy-related proteins

2021-09-13;

2021-12-01;

2021-12-02

國家自然科學(xué)基金項(xiàng)目(編號(hào)：31600934)資助[Supported by the National Natural Science Foundation of China (No. 31600934)]

劉靜，在讀碩士研究生，專業(yè)方向：細(xì)胞生物學(xué)。E-mail: 18428302536@163.com

許師明，博士，副教授，研究方向：心臟發(fā)育與疾病的分子機(jī)制。E-mail: xusm@e-mdic.cn

10.16288/j.yczz.21-329

(責(zé)任編委: 宋質(zhì)銀)