CCT2 is an aggrephagy receptor for clearance of solid protein aggregates

• DOI: 10.1016/j.cell.2022.03.005
• Publication Date: 2022-04-01T15:35:46Z
• Authors: Xinyu Ma; Caijing Lu; Yuting Chen; Shulin Li; Ningjia Ma; Xuan Tao; Ying Li; Jing Wang; Min Zhou; Yong-Bin Yan; Pilong Li; Kartoosh Heydari; Haiteng Deng; Min Zhang; Cong Yi; Liang Ge
• Keywords: 0301 basic medicine; Mice; Protein Aggregates; 03 medical and health sciences; Macroautophagy; Sequestosome-1 Protein; Autophagy; Animals; Apoptosis Regulatory Proteins; Carrier Proteins; Chaperonin Containing TCP-1

Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.