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首页> 外文期刊>Cell cycle >Loss of a membrane trafficking protein αSNAP induces non-canonical autophagy in human epithelia
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Loss of a membrane trafficking protein αSNAP induces non-canonical autophagy in human epithelia

机译：膜运输蛋白αSNAP的丢失诱导人上皮细胞非典型自噬

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Autophagy is a catabolic process that sequesters intracellular proteins and organelles within membrane vesicles called autophagosomes with their subsequent delivery to lyzosomes for degradation. This process involves multiple fusions of autophagosomal membranes with different vesicular compartments; however, the role of vesicle fusion in autophagosomal biogenesis remains poorly understood. This study addresses the role of a key vesicle fusion regulator, soluble N-ethylmaleimide-sensitive factor attachment protein α (αSNAP), in autophagy. Small interfering RNA-mediated downregulation of αSNAP expression in cultured epithelial cells stimulated the autophagic flux, which was manifested by increased conjugation of microtubule-associated protein light chain 3 (LC3-II) and accumulation of LC3-positive autophagosomes. This enhanced autophagy developed via a non-canonical mechanism that did not require beclin1-p150-dependent nucleation, but involved Atg5 and Atg7-mediated elongation of autophagosomal membranes. Induction of autophagy in αSNAP-depleted cells was accompanied by decreased mTOR signaling but appeared to be independent of αSNAP-binding partners, N-ethylmaleimide- sensitive factor and BNIP1. Loss of αSNAP caused fragmentation of the Golgi and downregulation of the Golgi-specific GTP exchange factors, GBF1, BIG1 and BIG2. Pharmacological disruption of the Golgi and genetic inhibition of GBF1 recreated the effects of αSNAP depletion on the autophagic flux. Our study revealed a novel role for αSNAP as a negative regulator of autophagy that acts by enhancing mTOR signaling and regulating the integrity of the Golgi complex.
机译：自噬是一种分解代谢过程，其将被称为自噬小体的膜囊泡中的细胞内蛋白质和细胞器隔离，随后将其递送至溶酶体进行降解。该过程涉及自噬体膜与不同囊泡区室的多次融合。然而，囊泡融合在自噬生物发生中的作用仍然知之甚少。这项研究解决了关键的囊泡融合调节剂，可溶性N-乙基马来酰亚胺敏感因子附着蛋白α（αSNAP）在自噬中的作用。小干扰RNA介导的培养的上皮细胞中αSNAP表达的下调刺激了自噬通量，这表现为微管相关蛋白轻链3（LC3-II）的缀合增加和LC3阳性自噬体的积累。这种增强的自噬通过非经典机制发展而来，该机制不需要beclin1-p150依赖性成核，但涉及Atg5和Atg7介导的自噬体膜的伸长。在αSNAP缺失的细胞中自噬的诱导伴随着mTOR信号的降低，但似乎独立于αSNAP结合伴侣，N-乙基马来酰亚胺敏感因子和BNIP1。 αSNAP的丢失会导致高尔基体碎裂和高尔基体特异性GTP交换因子GBF1，BIG1和BIG2的下调。高尔基体的药理学破坏和GBF1的遗传抑制重新产生了αSNAP耗尽对自噬通量的影响。我们的研究揭示了αSNAP作为自噬的负调节剂的新作用，该作用通过增强mTOR信号传导和调节高尔基复合体的完整性发挥作用。

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