CCT2 is an aggrephagy receptor for clearance of solid protein aggregates

• Published in: Cell 2022-04, Vol.185 (8), p.1325-1345.e22
• Main Authors: Ma, Xinyu, Lu, Caijing, Chen, Yuting, Li, Shulin, Ma, Ningjia, Tao, Xuan, Li, Ying, Wang, Jing, Zhou, Min, Yan, Yong-Bin, Li, Pilong, Heydari, Kartoosh, Deng, Haiteng, Zhang, Min, Yi, Cong, Ge, Liang
• Format: Article
• Language: English
• Subjects: aggrephagy; Animals; Apoptosis Regulatory Proteins - metabolism; autophagy; Autophagy - physiology; Carrier Proteins - metabolism; CCT2; chaperone; chaperonin; Chaperonin Containing TCP-1 - metabolism; FUS; GABARAP; huntingtin; Huntington’s disease; LC3; Macroautophagy; Mice; NBR1; neurodegeneration; P62; phase separation; Protein Aggregates; protein aggregation; Sequestosome-1 Protein - metabolism; SOD1; tau; TAX1BP1; TRiC
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.03.005

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. [Display omitted] •CCT2 regulates aggrephagy via associating with ATG8s and aggregation-prone proteins•CCT2 functions independently of ubiquitin-binding autophagy receptors•CCT2 enables autophagy-mediated clearance of solid protein aggregates•CCT2 monomer formation acts as a switch of function from chaperone to autophagy Here, we identify the chaperonin TRiC subunit CCT2 as an aggrephagy receptor specific for the clearance of solid protein aggregates, which provides an implication for the understanding and treatment of human diseases associated with protein aggregation.