機(jī)體自噬途徑靈活多樣，是因?yàn)樽允尚◇w的與晚期內(nèi)體/溶酶體的融合過(guò)程中涉及多種復(fù)合物和拴系蛋白，而這些復(fù)合物和拴系蛋白的功能部分是多余的，因此這一過(guò)程具有一定的代償性，當(dāng)一個(gè)因子缺失導(dǎo)致的自噬受損可通過(guò)其他機(jī)制來(lái)促進(jìn)自噬，有助于維持細(xì)胞穩(wěn)態(tài)?？梢?jiàn)自噬對(duì)維持機(jī)體健康非常重要。

多種人類(lèi)疾病的發(fā)病機(jī)制都與自噬溶酶體形成受損有關(guān)，目前研究最多的是神經(jīng)退行性疾病和癌癥。

神經(jīng)性退行性疾病中，溶酶體功能受損與發(fā)病機(jī)制密切相關(guān)。疾病蛋白（如帕金森病中的α-突觸核蛋白）累積將TFEB隔離在細(xì)胞質(zhì)中，損害溶酶體功能，影響自噬小體與溶酶體融合[1]。神經(jīng)性退行性疾病重要標(biāo)志物如阿爾茨海默病中的a β和Tau蛋白，帕金森病中的α-突觸核蛋白和亨廷頓病中的亨廷頓蛋白等，以及病理性多聚谷氨酰胺擴(kuò)增，可誘導(dǎo)受體細(xì)胞內(nèi)的溶酶體破裂[2]，影響自噬發(fā)生。

直接參與自噬溶酶體形成的基因突變也會(huì)導(dǎo)致某些神經(jīng)元群體的選擇性損傷，不同基因突變導(dǎo)致不同的疾?。▓D1）。如CHMP2B突變導(dǎo)致內(nèi)體功能受損引起額顳葉癡呆和肌萎縮性側(cè)索硬化癥，PS1突變導(dǎo)致溶酶體酸化受阻引起阿爾茨海默病[3]。而在溶酶體形成過(guò)程中，EPG5、WDR45和WDR45B突變或缺失是導(dǎo)致神經(jīng)退行性疾病的主要原因。EPG5基因敲除小鼠可重現(xiàn)Vici綜合征患者的神經(jīng)發(fā)育特征，表現(xiàn)出運(yùn)動(dòng)神經(jīng)元的選擇性缺失[4]。WDR45基因敲除小鼠表現(xiàn)出學(xué)習(xí)和記憶障礙，可觀察到軸突腫脹[5]。在WDR45B基因敲除小鼠中，同樣出現(xiàn)了軸突腫脹的現(xiàn)象，另外還可觀察到小腦萎縮，表現(xiàn)出異常的運(yùn)動(dòng)行為和認(rèn)知障礙[6]。

圖1 自噬溶酶體形成異常與神經(jīng)退行性疾病[3]

癌癥中，自噬通路受損后受損的細(xì)胞器和有毒蛋白無(wú)法及時(shí)清除，在細(xì)胞中不斷累積，最終促進(jìn)癌癥的發(fā)生發(fā)展。另外，有研究發(fā)現(xiàn)在晚期腫瘤或癌癥治療過(guò)程中，高自噬水平提高了腫瘤細(xì)胞在缺氧和代謝應(yīng)激等惡劣條件下的生存率。轉(zhuǎn)錄因子TFEB活性增強(qiáng)促進(jìn)溶酶體胞吐，將組織蛋白酶等蛋白水解酶釋放到細(xì)胞微環(huán)境中，促進(jìn)細(xì)胞外基質(zhì)重塑，從而刺激癌細(xì)胞侵襲和轉(zhuǎn)移[7]。上文提到的EPG5和WDR45表達(dá)水平變化也會(huì)促進(jìn)癌細(xì)胞增殖[8-9]。

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除疾病蛋白突變外，病原體感染也會(huì)導(dǎo)致自噬溶酶體形成受阻（圖2）。正常情況下，自噬通過(guò)捕獲入侵的病原體并將其運(yùn)送到溶酶體進(jìn)行降解（這一過(guò)程稱(chēng)為異自噬）來(lái)應(yīng)對(duì)入侵的病原體，這有助于抗原呈遞，從而激活固有和適應(yīng)性免疫應(yīng)答。為逃避機(jī)體免疫，病原體進(jìn)化出了不同機(jī)制來(lái)抑制自噬，可利用自噬小體促進(jìn)其在細(xì)胞內(nèi)的生存和生長(zhǎng)，進(jìn)行病毒復(fù)制并釋放到機(jī)體中，進(jìn)而阻斷可降解的自噬溶酶體的形成[10-12]。

圖2 病原體抑制自噬溶酶體的形成[3]

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關(guān)于大自噬-自噬溶酶體的介紹就到這里啦，下期開(kāi)始介紹細(xì)胞器自噬相關(guān)內(nèi)容~

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漢恒生物專(zhuān)營(yíng)工具病毒十余載，可定制自噬通路相關(guān)基因的過(guò)表達(dá)/干擾的質(zhì)粒以及病毒工具等產(chǎn)品，如有技術(shù)問(wèn)題或產(chǎn)品訂購(gòu)需求，歡迎咨詢(xún)！

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參考文獻(xiàn)

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[2]?Flavin, William P., Flavin, William P., Bousset, Luc., Green, Zachary C., Chu, Yaping.. ?Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins. Acta neuropathologica, 2017, 134(4):629-653.

[3]?Zhao, Yan G., Codogno, Patrice., Zhang, Hong., Zhang, Hong.. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nature reviews. Molecular cell biology, 2021, 22(11):733-750.

[4]?Cullup, Thomas., Kho, Ay Lin., Dionisi-Vici, Carlo., Brandmeier, Birgit., Smith, Frances.. ?Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature genetics, 2012, 45(1):83-7.

[5]?Zhao, Yan G., Sun, Le., Miao, Guangyan., Ji, Cuicui., Zhao, Hongyu.. The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. Autophagy, 2015, 11(6):881-90.

[6]?Zhao, Yan G., Sun, Le., Miao, Guangyan., Ji, Cuicui., Zhao, Hongyu.. The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. Autophagy, 2015, 11(6):881-90.

[7]?Kundu, Samrat T., Grzeskowiak, Caitlin L., Fradette, Jared J., Gibson, Laura A., Rodriguez, Leticia B.. TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. Nature communications, 2018, 9(1):2731.

[8]?Kundu, Samrat T., Grzeskowiak, Caitlin L., Fradette, Jared J., Gibson, Laura A., Rodriguez, Leticia B.. TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. Nature communications, 2018, 9(1):2731.

[9]?Bai, Mixue., Che, Yingying., Lu, Kun., Fu, Lin.. Analysis of deubiquitinase OTUD5 as a biomarker and therapeutic target for cervical cancer by bioinformatic analysis. PeerJ, 2020, 8:e9146.

[10]?Corona, Abigail K., Saulsbery, Holly M., Corona Velazquez, Angel F., Jackson, William T.. ?Enteroviruses Remodel Autophagic Trafficking through Regulation of Host SNARE Proteins to Promote Virus Replication and Cell Exit. Cell reports, 2018, 22(12):3304-3314.

[11]?Mohamud, Yasir., Shi, Junyan., Qu, Junyan., Poon, Tak., Xue, Yuan Chao.. Enteroviral Infection Inhibits Autophagic Flux via Disruption of the SNARE Complex to Enhance Viral Replication. Cell reports, 2018, 22(12):3292-3303.

[12]?Kemball, Christopher C., Alirezaei, Mehrdad., Flynn, Claudia T., Wood, Malcolm R., Harkins, Stephanie.. Coxsackievirus infection induces autophagy-like vesicles and megaphagosomes in pancreatic acinar cells in vivo. Journal of virology, 2010, 84(23):12110-24.