The deubiquitinase USP11 is a versatile and conserved regulator of autophagy.
The deubiquitinase USP11 is a versatile and conserved regulator of autophagy.
复制标题
DOI：
10.1016/j.jbc.2021.101263
复制
发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Bremm A
中科院分区：
文献类型：
--
作者：
Basic M;Hertel A;Bajdzienko J;Bonn F;Tellechea M;Stolz A;Kern A;Behl C;Bremm A
自噬是一种主要的细胞质量控制系统，负责蛋白质和细胞器的降解，以应对应激和损伤，以维持稳态。自噬相关蛋白或调节组分的泛素化对于精确控制自噬途径是重要的。在这里，我们表明去遍在蛋白酶遍在蛋白特异性蛋白酶11（USP 11）限制自噬，并且哺乳动物细胞中USP 11的KO导致自噬通量升高。我们还证明，在秀丽隐杆线虫中USP 11同源物H34C03.2的耗尽触发了自噬的超活化，并保护动物免受人淀粉样β肽42聚集诱导的麻痹。USP 11与自噬特异性III类磷脂酰肌醇3-激酶复合物I共沉淀，并限制其与核受体结合因子2的相互作用，从而降低III类磷脂酰肌醇3-激酶复合物I的脂质激酶活性，并随后将效应物如WD重复结构域磷酸肌醇相互作用蛋白募集至自噬体膜。因此，在USP 11 KO细胞中积累了更多的WD重复结构域磷酸肌醇相互作用蛋白2斑点。此外，USP 11与雷帕霉素的丝氨酸/苏氨酸激酶机制靶点相互作用并使其稳定，从而进一步促进自噬诱导的调节。总之，我们的数据表明，USP 11在多个位点影响自噬途径，抑制USP 11可减轻蛋白毒性症状，这是神经退行性疾病的主要标志。
Autophagy is a major cellular quality control system responsible for the degradation of proteins and organelles in response to stress and damage to maintain homeostasis. Ubiquitination of autophagy-related proteins or regulatory components is important for the precise control of autophagy pathways. Here, we show that the deubiquitinase ubiquitin-specific protease 11 (USP11) restricts autophagy and that KO of USP11 in mammalian cells results in elevated autophagic flux. We also demonstrate that depletion of the USP11 homolog H34C03.2 in Caenorhabditis elegans triggers hyperactivation of autophagy and protects the animals against human amyloid-β peptide 42 aggregation-induced paralysis. USP11 coprecipitated with autophagy-specific class III phosphatidylinositol 3-kinase complex I and limited its interaction with nuclear receptor-binding factor 2, thus decreasing lipid kinase activity of class III phosphatidylinositol 3-kinase complex I and subsequent recruitment of effectors such as WD-repeat domain phosphoinositide-interacting proteins to the autophagosomal membrane. Accordingly, more WD-repeat domain phosphoinositide-interacting protein 2 puncta accumulated in USP11 KO cells. In addition, USP11 interacts with and stabilizes the serine/threonine kinase mechanistic target of rapamycin, thereby further contributing to the regulation of autophagy induction. Taken together, our data suggested that USP11 impinges on the autophagy pathway at multiple sites and that inhibiting USP11 alleviates symptoms of proteotoxicity, which is a major hallmark of neurodegenerative diseases.
登录
查看更多内容
影响因子：
16.6
作者：
Lu, Jiahong;He, Liqiang;Behrends, Christian;Araki, Masatake;Araki, Kimi;Wang, Qing Jun;Catanzaro, Joseph M.;Friedman, Scott L.;Zong, Wei-Xing;Fiel, M. Isabel;Li, Min;Yue, Zhenyu
通讯作者：
Yue, Zhenyu
影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
通讯作者：
Carpenter AE
影响因子：
13.3
作者：
Ohashi Y;Soler N;García Ortegón M;Zhang L;Kirsten ML;Perisic O;Masson GR;Burke JE;Jakobi AJ;Apostolakis AA;Johnson CM;Ohashi M;Ktistakis NT;Sachse C;Williams RL
通讯作者：
Williams RL
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
16.6
作者：
Park, Mi Kyung;Yao, Yixin;Song, Min Sup
通讯作者：
Song, Min Sup