A20 binding and inhibitor of nuclear factor kappa B (NF-κB)-1 (ABIN-1): a novel modulator of mitochondrial autophagy.
A20 binding and inhibitor of nuclear factor kappa B (NF-κB)-1 (ABIN-1): a novel modulator of mitochondrial autophagy.
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A20 结合和核因子 kappa B (NF-κB)-1 (ABIN-1) 抑制剂：一种新型线粒体自噬调节剂。
DOI：
10.1152/ajpcell.00493.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Scha
中科院分区：
文献类型：
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作者：
Merline,Rosetta;Rödig,Heiko;Zeng-Brouwers,Jinyang;Poluzzi,Chiara;Tascher,Georg;Michaelis,Jonas;Lopez-Mosqueda,Jaime;Rhiner,Andrew;Huber,LisaSophie;Diehl,Valentina;Dikic,Ivan;Kögel,Donat;Münch,Christian;Wygrecka,Malgorzata;Scha
核因子κB (NF-κB)-1 （ABIN-1）的A20结合抑制剂是一种多泛素结合蛋白，是一种信号诱导的自噬受体，可减弱NF-κB介导的炎症和细胞死亡。本研究旨在阐明ABIN-1在线粒体自噬中的潜在作用，这是一个生物学过程，其结果在多种生理和病理环境中具有决定性作用。发现微管相关蛋白1A/1B轻链3B-II （LC3B-II）与异位表达的血凝素(HA)-标记的全长(FL)-ABIN-1复合物。细菌表达ABIN-1和LC3A和LC3B表明ABIN-1与LC3蛋白直接结合，而ABIN-1的LC3相互作用区（LIR） 1和2基序的突变取消了ABIN-1/LC3B- ii复合物的形成。重要的是，在HeLa细胞中诱导自噬导致ABIN-1与自噬体中的LC3B-II和自噬溶酶体中溶酶体相关膜蛋白1 （LAMP-1）共定位，导致ABIN-1与p62降解。有趣的是，在HeLa-mCherry-Parkin转染的细胞中，ABIN-1被发现转运到受损的线粒体。与此观察结果一致，聚集规律间隔短回传重复序列(CRISPR)/CRISPR相关蛋白9 （Cas9）介导的ABIN-1缺失显著抑制了线粒体外膜蛋白电压依赖性阴离子选择通道1 （VDAC-1）、丝裂酶-2 （MFN2）和线粒体外膜转位酶（TOM）20的降解。此外，短干扰RNA （siRNA）介导的ABIN-1敲低显著降低了表达mCherry-Parkin和荧光报告基因mt-mKEIMA的HeLa细胞对线粒体的溶酶体摄取。总的来说，我们的研究结果确定了ABIN-1是一种新的、选择性的线粒体自噬调节剂，可以促进线粒体自噬，从而为调节线粒体稳态的复杂细胞机制增加了一个新的参与者。
A20 binding inhibitor of nuclear factor kappa B (NF-κB)-1 (ABIN-1), a polyubiquitin-binding protein, is a signal-induced autophagy receptor that attenuates NF-κB-mediated inflammation and cell death. The present study aimed to elucidate the potential role of ABIN-1 in mitophagy, a biological process whose outcome is decisive in diverse physiological and pathological settings. Microtubule-associated proteins 1A/1B light chain 3B-II (LC3B-II) was found to be in complex with ectopically expressed hemagglutinin (HA)-tagged-full length (FL)-ABIN-1. Bacterial expression of ABIN-1 and LC3A and LC3B showed direct binding of ABIN-1 to LC3 proteins, whereas mutations in the LC3-interacting region (LIR) 1 and 2 motifs of ABIN-1 abrogated ABIN-1/LC3B-II complex formation. Importantly, induction of autophagy in HeLa cells resulted in colocalization of ABIN-1 with LC3B-II in autophagosomes and with lysosomal-associated membrane protein 1 (LAMP-1) in autophagolysosomes, leading to degradation of ABIN-1 with p62. Interestingly, ABIN-1 was found to translocate to damaged mitochondria in HeLa-mCherry-Parkin transfected cells. In line with this observation, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated deletion of ABIN-1 significantly inhibited the degradation of the mitochondrial outer membrane proteins voltage-dependent anion-selective channel 1 (VDAC-1), mitofusin-2 (MFN2), and translocase of outer mitochondrial membrane (TOM)20. In addition, short interfering RNA (siRNA)-mediated knockdown of ABIN-1 significantly decreased lysosomal uptake of mitochondria in HeLa cells expressing mCherry-Parkin and the fluorescence reporter mt-mKEIMA. Collectively, our results identify ABIN-1 as a novel and selective mitochondrial autophagy regulator that promotes mitophagy, thereby adding a new player to the complex cellular machinery regulating mitochondrial homeostasis.