1] Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA [2] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California 94143, USA.
Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
Nat Cell Biol. 2015 Mar;17(3):300-10. doi: 10.1038/ncb3112. Epub 2015 Feb 16.
The ubiquitin-like molecule ATG12 is required for the early steps of autophagy. Recently, we identified ATG3, the E2-like enzyme required for LC3 lipidation during autophagy, as an ATG12 conjugation target. Here, we demonstrate that cells lacking ATG12-ATG3 have impaired basal autophagic flux, accumulation of perinuclear late endosomes, and impaired endolysosomal trafficking. Furthermore, we identify an interaction between ATG12-ATG3 and the ESCRT-associated protein Alix (also known as PDCD6IP) and demonstrate that ATG12-ATG3 controls multiple Alix-dependent processes including late endosome distribution, exosome biogenesis and viral budding. Similar to ATG12-ATG3, Alix is functionally required for efficient basal, but not starvation-induced, autophagy. Overall, these results identify a link between the core autophagy and ESCRT machineries and uncover a role for ATG12-ATG3 in late endosome function that is distinct from the canonical role of either ATG in autophagosome formation.
泛素样分子 ATG12 是自噬早期步骤所必需的。最近，我们鉴定出 ATG3，即自噬过程中 LC3 脂质化所需的 E2 样酶，是 ATG12 连接的靶标。在这里，我们证明缺乏 ATG12-ATG3 的细胞会导致基础自噬通量受损、核周晚期内体积累以及内溶酶体运输受损。此外，我们发现 ATG12-ATG3 与 ESCRT 相关蛋白 Alix（也称为 PDCD6IP）之间存在相互作用，并证明 ATG12-ATG3 控制多个依赖 Alix 的过程，包括晚期内体分布、外泌体生物发生和病毒出芽。与 ATG12-ATG3 相似，Alix 对于有效的基础自噬（但不是饥饿诱导的自噬）是功能必需的。总的来说，这些结果表明核心自噬和 ESCRT 机器之间存在联系，并揭示了 ATG12-ATG3 在晚期内体功能中的作用，这与 ATG 在自噬体形成中的典型作用不同。
