TNFAIP8L2/TIPE2 impairs autolysosome reformation via modulating the RAC1-MTORC1 axis
TNFAIP8L2/TIPE2 impairs autolysosome reformation via modulating the RAC1-MTORC1 axis
复制标题
TNFAIP8L2/TIPE2 通过调节 RAC1-MTORC1 轴损害自溶酶体重组
DOI：
10.1080/15548627.2020.1761748
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发表时间：
2020-05-29
期刊：
影响因子：
13.3
通讯作者：
Zhang, Lining
中科院分区：
文献类型：
--
作者：
Li, Wen;Li, Yulan;Zhang, Lining
摘要自噬是一个进化上保守的过程，它涉及溶酶体内细胞质组分的选择性降解以响应饥饿。自噬是一种古老的防御机制，与免疫系统紧密结合，对先天免疫和适应性免疫具有多重作用。促炎细胞因子和抗炎细胞因子可以分别激活和抑制自噬。TNFAIP 8L 2/TIPE 2（tumor necrosis factor，α-induced protein 8-like 2）是一种新发现的天然免疫和获得性免疫的负调节因子，在免疫稳态中起重要作用。然而，TNFAIP 8L 2是否以及如何控制自噬仍然是未知的。鼠TNFAIP 8L 2可以直接结合并阻断RAC 1 GT3活性以调节先天免疫。RAC 1也可以结合MTOR并调节MTOR 1的细胞定位和活性。在这里，我们发现TNFAIP 8L 2可以与MTOR竞争结合到RAC 1的GTP结合状态，并负调节MTOR 1活性。有趣的是，TNFAIP 8L 2过表达不能通过在谷氨酰胺和血清饥饿下抑制MTOR活性来诱导自噬通量。相反，TNFAIP 8L 2似乎在长时间饥饿期间损害自噬溶酶体重组（ALR）。最后，我们证明TNFAIP 8L 2过表达导致MTOR再激活缺陷并破坏自噬通量，从而导致细胞死亡。此外，TNFAIP 8L 2缺陷可通过控制LPS诱导的小鼠内毒素血症模型中的MTOR活性而加剧炎症反应和肺损伤。我们的研究揭示了TNFAIP 8L 2通过调节RAC 1-MTORC 1轴在自噬中的新作用，这支持其作为治疗性治疗靶点的潜力。微管相关蛋白1轻链3 β; MTORC 1：雷帕霉素激酶复合物1的机制靶点; RAPA：雷帕霉素; RPS 6：核糖体蛋白S6; SQSTM 1/p62：多价螯合体1; Starv：饥饿; TNFAIP 8L 2/TIPE 2：肿瘤坏死因子-α诱导的蛋白-8样-2。
ABSTRACT Macroautophagy/autophagy is an evolutionarily conserved process that involves the selective degradation of cytoplasmic components within lysosomes in response to starvation. Autophagy is an ancient defense mechanism that has been closely integrated with the immune system and has multiple effects on innate and adaptive immunity. The pro-inflammatory and anti-inflammatory cytokines can activate and inhibit autophagy, respectively. TNFAIP8L2/TIPE2 (tumor necrosis factor, alpha-induced protein 8-like 2) is a newly identified immune negative regulator of innate and adaptive immunity that plays an important role in immune homeostasis. However, whether and how TNFAIP8L2 controls autophagy is still unknown. Murine TNFAIP8L2 can directly bind to and block the RAC1 GTPase activity to regulate innate immunity. RAC1 can also bind to MTOR and regulate MTORC1 cellular localization and activity. Here, we find that TNFAIP8L2 can compete with MTOR for binding to the GTP-bound state of RAC1 and negatively regulate MTORC1 activity. Interestingly, TNFAIP8L2 overexpression fails to induce autophagy flux by the suppression of the MTOR activity under glutamine and serum starvation. Instead, TNFAIP8L2 appears to impair autophagic lysosome reformation (ALR) during prolonged starvation. Finally, we demonstrate that TNFAIP8L2 overexpression leads to a defect in MTOR reactivation and disrupts autophagy flux, thereby leading to cell death. Furthermore, TNFAIP8L2 deficiency can exacerbate the inflammatory response and lung injury by controlling the MTOR activity in an LPS-induced mouse endotoxemia model. Our study reveals a novel role of TNFAIP8L2 in autophagy by regulating the RAC1-MTORC1 axis that supports its potential as a target for therapeutic treatment.Abbreviations: ALR: autophagic lysosome reformation; BafA1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; Co-IP: Co-Immunoprecipitation; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; RAPA: rapamycin; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; Starv: Starvation; TNFAIP8L2/TIPE2: tumor necrosis factor-alpha-induced protein-8 like-2.