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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
Published on: August 28, 2012
CCT2 is an aggrephagy receptor for clearance of solid protein aggregates
Xinyu Ma1, Caijing Lu1, Yuting Chen2
1State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
Abstract:
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.
Insights
Researchers discovered CCT2 as a novel autophagy receptor. This protein selectively clears solid protein aggregates, offering new insights into neurodegenerative disease mechanisms.
Area of Science:
- Cell Biology
- Molecular Biology
- Neuroscience
Background:
- Protein aggregation is implicated in numerous human diseases.
- Autophagy, specifically aggrephagy, is the cellular mechanism for degrading protein aggregates.
- The precise mechanisms governing selective protein aggregate clearance by autophagy remain unclear.
Purpose of the Study:
- To identify novel autophagy receptors involved in the selective degradation of protein aggregates.
- To elucidate the mechanism by which CCT2 regulates aggrephagy.
- To investigate the role of CCT2 in clearing aggregation-prone proteins in cellular and in vivo models.
Main Methods:
- Identification of CCT2 as an autophagy receptor.
- Analysis of CCT2 interaction with aggregation-prone proteins and ATG8s.
- Assessment of CCT2's role in aggrephagy independently of other known receptors.
- Investigation of CCT2's functional switch in response to protein aggregation.
Main Results:
- CCT2 acts as an autophagy receptor that targets aggregation-prone proteins for clearance.
- CCT2 binds to protein aggregates independently of ubiquitination and interacts with ATG8s via a VLIR motif.
- CCT2 specifically degrades solid protein aggregates, distinct from the liquid condensate clearance by P62, NBR1, and TAX1BP1.
- Accumulation of aggregation-prone proteins triggers CCT2's transition from a chaperone to an autophagy receptor.
Conclusions:
- CCT2 is a novel autophagy receptor crucial for the selective clearance of solid protein aggregates.
- CCT2's unique mechanism of action provides new therapeutic targets for protein aggregation diseases.
- Understanding CCT2's role advances knowledge of aggrephagy and its implications in pathology.
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