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TNF 诱导的坏死性凋亡通过 RIPK3 依赖性 AMPK 激活引发早期自噬事件，但抑制晚期自噬。

TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy.

机构信息

Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

DWI-Leibniz Institute for Interactive Materials, Aachen, Germany.

出版信息

Autophagy. 2021 Dec;17(12):3992-4009. doi: 10.1080/15548627.2021.1899667. Epub 2021 Mar 28.

DOI:10.1080/15548627.2021.1899667
PMID:33779513
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8726653/
Abstract

Macroautophagy/autophagy and necroptosis represent two opposing cellular s tress responses. Whereas autophagy primarily fulfills a cyto-protective function, necroptosis is a form of regulated cell death induced via death receptors. Here, we aimed at investigating the molecular crosstalk between these two pathways. We observed that RIPK3 directly associates with AMPK and phosphorylates its catalytic subunit PRKAA1/2 at T183/T172. Activated AMPK then phosphorylates the autophagy-regulating proteins ULK1 and BECN1. However, the lysosomal degradation of autophagosomes is blocked by TNF-induced necroptosis. Specifically, we observed dysregulated SNARE complexes upon TNF treatment; e.g., reduced levels of full-length STX17. In summary, we identified RIPK3 as an AMPK-activating kinase and thus a direct link between autophagy- and necroptosis-regulating kinases. ACACA/ACC: acetyl-CoA carboxylase alpha; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BECN1: beclin 1; GFP: green fluorescent protein; EBSS: Earle's balanced salt solution; Hs: ; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain like pseudokinase; Mm: ; MTOR: mechanistic target of rapamycin kinase; MVB: multivesicular body; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PLA: proximity ligation assay; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKAA2: protein kinase AMP-activated catalytic subunit alpha 2; PRKAB2: protein kinase AMP-activated non-catalytic subunit beta 2; PRKAG1: protein kinase AMP-activated non-catalytic subunit gamma 1; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; STX7: syntaxin 7; STX17: syntaxin 17; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; WT: wild-type.

摘要

自噬和坏死性凋亡代表两种相反的细胞应激反应。自噬主要发挥细胞保护功能，而坏死性凋亡是通过死亡受体诱导的一种受调控的细胞死亡形式。在这里，我们旨在研究这两种途径之间的分子相互作用。我们观察到 RIPK3 直接与 AMPK 结合，并在 T183/T172 位点磷酸化其催化亚基 PRKAA1/2。激活的 AMPK 然后磷酸化自噬调节蛋白 ULK1 和 BECN1。然而，TNF 诱导的坏死性凋亡会阻断自噬小体的溶酶体降解。具体来说，我们在 TNF 处理后观察到调节紊乱的 SNARE 复合物；例如，全长 STX17 的水平降低。总之，我们确定 RIPK3 是一种 AMPK 激活激酶，因此是自噬和坏死性凋亡调节激酶之间的直接联系。ACACA/ACC：乙酰辅酶 A 羧化酶 alpha；AMPK：AMP 激活的蛋白激酶；ATG：自噬相关；BECN1：beclin 1；GFP：绿色荧光蛋白；EBSS：Earle 的平衡盐溶液；Hs：；KO：敲除；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MEF：小鼠胚胎成纤维细胞；MLKL：混合谱系激酶结构域样假激酶；Mm：；MTOR：雷帕霉素靶蛋白激酶；MVB：多泡体；PIK3C3/VPS34：磷脂酰肌醇 3-激酶催化亚基 3；PIK3R4/VPS15：磷酸肌醇-3-激酶调节亚基 4；PLA：邻近连接分析；PRKAA1：蛋白激酶 AMP 激活的催化亚基 alpha 1；PRKAA2：蛋白激酶 AMP 激活的催化亚基 alpha 2；PRKAB2：蛋白激酶 AMP 激活的非催化亚基 beta 2；PRKAG1：蛋白激酶 AMP 激活的非催化亚基 gamma 1；PtdIns3K：磷脂酰肌醇 3-激酶；PtdIns3P：磷脂酰肌醇-3-磷酸；RIPK1：受体相互作用丝氨酸/苏氨酸激酶 1；RIPK3：受体相互作用丝氨酸/苏氨酸激酶 3；SNAP29：突触相关蛋白 29；SNARE：可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体；SQSTM1/p62：自噬体相关蛋白 1；STK11/LKB1：丝氨酸/苏氨酸激酶 11；STX7：突触融合蛋白 7；STX17：突触融合蛋白 17；TAX1BP1：Tax1 结合蛋白 1；TNF：肿瘤坏死因子；ULK1：非典型卷曲相关激酶 1；VAMP8：囊泡相关膜蛋白 8；WT：野生型。

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