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Abstract：
Canonical autophagy is an evolutionarily conserved process that forms double-membrane structures and mediates the degradation of long-lived proteins (LLPs). Noncanonical autophagy (NCA) is an important alternative pathway involving the formation of microtubule-associated protein 1 light chain 3 (LC3)-positive structures that are independent of partial core autophagy proteins. NCA has been defined by the conjugation of ATG8s to single membranes (CASM). During canonical autophagy and NCA/CASM, LC3 undergoes a lipidation modification, and ATG16L1 is a crucial protein in this process. Previous studies have reported that the WDR domain of ATG16L1 is not necessary for canonical autophagy. However, our study found that WDR domain deficiency significantly impaired LLP degradation in basal conditions and slowed down LC3-II accumulation in canonical autophagy. We further demonstrated that the observed effect was due to a reduced interaction between ATG16L1 and FIP200/WIPI2, without affecting lysosome function or fusion. Furthermore, we also found that the WDR domain of ATG16L1 is crucial for chemical-induced NCA/CASM. The results showed that removing the WDR domain or introducing the K490A mutation in ATG16L1 significantly inhibited the NCA/CASM, which interrupted the V-ATPase-ATG16L1 axis. In conclusion, this study highlights the significance of the WDR domain of ATG16L1 for both canonical autophagy and NCA functions, improving our understanding of its role in autophagy.
摘要：
典型自噬是一种进化上保守的过程，形成双膜结构并介导长寿命蛋白质（LLP）的降解。非经典自噬（NCA）是一种重要的替代途径，涉及微管相关蛋白1轻链3（LC3）阳性结构的形成，该结构独立于部分核心自噬蛋白。NCA已通过ATG8与单膜(CASM)的缀合来定义。在规范自噬和NCA/CASM期间，LC3经历脂化修饰，ATG16L1是这个过程中的关键蛋白质。先前的研究报道ATG16L1的WDR域不是经典自噬所必需的。然而,我们的研究发现,WDR结构域缺陷显著损害了LLP在基础条件下的降解,并减缓了LC3-II在经典自噬中的积累.我们进一步证明，观察到的效果是由于ATG16L1和FIP200/WIPI2之间的相互作用减少，而不影响溶酶体功能或融合。此外，我们还发现ATG16L1的WDR结构域对于化学诱导的NCA/CASM至关重要。结果表明，在ATG16L1中去除WDR结构域或引入K490A突变显著抑制NCA/CASM，中断了V-ATPase-ATG16L1轴。总之,这项研究强调了ATG16L1的WDR域对规范自噬和NCA功能的意义，提高我们对其在自噬中的作用的理解。
