RACK1 Promotes Autophagy by Enhancing the Atg14L-Beclin1-Vps34-Vps15 Complex Formation upon Phosphorylation by AMPK
RACK1 Promotes Autophagy by Enhancing the Atg14L-Beclin1-Vps34-Vps15 Complex Formation upon Phosphorylation by AMPK
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DOI：
10.1016/j.celrep.2015.10.011
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发表时间：
2015-11-17
期刊：
影响因子：
8.8
通讯作者：
Zhang, Jiyan
中科院分区：
文献类型：
--
作者：
Zhao, Yawei;Wang, Qingyang;Zhang, Jiyan
自噬对于维持组织内环境稳定是必不可少的。虽然衔接子已被证明可以促进Atg 14 L-Beclin 1-Vps 34-Vps 15复合物的组装，该复合物在自噬体形成中起作用，但自噬机制是否主动招募此类衔接子仍然未知。WD 40重复序列蛋白是一个大的、高度保守的衔接子家族，参与各种细胞活动。然而，WD 40重复蛋白，如RACK 1，在出生后哺乳动物生理学中的作用仍然未知。在这里，我们报告说，肝细胞特异性RACK 1缺陷导致肝脏中的脂质积累，伴随着受损的Atg 14 L-连接的Vps 34活性和自噬。进一步的研究表明，RACK 1参与了自噬体生物合成复合物的形成，其磷酸化AMPK在Thr 50。RACK 1的Thr 50磷酸化增强了其与Vps 15，Atg 14 L和Beclin 1的直接结合，从而促进了自噬起始复合物的组装。这些观察结果提供了深入了解自噬诱导，并建立了RACK 1在出生后哺乳动物生理学中的关键作用。
Autophagy is essential for maintaining tissue homeostasis. Although adaptors have been demonstrated to facilitate the assembly of the Atg14L-Beclin 1-Vps34-Vps15 complex, which functions in autophagosome formation, it remains unknown whether the autophagy machinery actively recruits such adaptors. WD40-repeat proteins are a large, highly conserved family of adaptors implicated in various cellular activities. However, the role of WD40-repeat-only proteins, such as RACK1, in postnatal mammalian physiology remains unknown. Here, we report that hepatocyte specific RACK1 deficiency leads to lipid accumulation in the liver, accompanied by impaired Atg14L-linked Vps34 activity and autophagy. Further exploration indicates that RACK1 participates in the formation of autophagosome biogenesis complex upon its phosphorylation by AMPK at Thr50. Thr50 phosphorylation of RACK1 enhances its direct binding to Vps15, Atg14L, and Beclin 1, thereby promoting the assembly of the autophagy-initiation complex. These observations provide insight into autophagy induction and establish a pivotal role for RACK1 in postnatal mammalian physiology.