错误折叠蛋白的堆积形成毒性蛋白聚集体，是导致很多人类疾病的原因，例如：神经退行性疾病、眼部病变、II型糖尿病等。在细胞内，蛋白聚集体可以被细胞自噬选择性清除，这一过程称为聚集体自噬。选择性自噬是神经退行性疾病的一个潜在治疗靶点。然而，自噬体选择性识别蛋白聚集体的具体机制一直不清楚。虽然多项研究表明，一些泛素结合受体(包括：P62、NBR1和TAX1BP1等)负责将自噬体膜募集到蛋白聚集体上从而介导其自噬性清除，但是由于这些泛素结合受体的本质是识别泛素链，它们并不特异性地介导聚集体自噬，而是与其他类型的选择性自噬共享，例如：线粒体自噬、病原菌自噬和溶酶体自噬等。酵母和线虫中已被报导存在特异性聚集体自噬受体，但是哺乳动物细胞中是否存在特异性聚集体自噬受体尚不明确。在本文的研究中，我们发现分子伴侣Chaperonin复合体的亚基CCT2作为一种新型的自噬受体介导多种聚集体蛋白的清除。一方面，CCT2能够与聚集体蛋白结合，并且不依赖于聚集体蛋白的泛素化；另一方面，CCT2通过一个非经典的VLIR结构域与自噬体的标记蛋白ATG8结合。CCT2介导的聚集体自噬不依赖于已知的泛素结合受体(P62, NBR1, 和TAX1BP1)或分子伴侣介导的自噬(Chaperone-mediated autophagy，CMA)，是一种新的聚集体自噬途径。不同于已知的受体P62、NBR1和TAX1BP1，CCT2 更倾向于促进固态而非液态聚集体的自噬性降解，使其在病理条件下更具优势。机制研究发现，聚集体蛋白可以促进CCT2单体的形成，使其暴露出与ATG8的结合位点VLIR，从而促使CCT2从分子伴侣到自噬受体功能的转变。除了CCT2，我们还发现了多种分子伴侣蛋白可以促进聚集体的自噬性清除，揭示了分子伴侣在防止蛋白聚集体积累与维持蛋白稳态方面的新角色。本项研究发现了CCT2作为聚集体自噬受体清除固态聚集体的作用，为治疗多种由蛋白聚集引起的人类疾病提供了一个新的思路。
Misfolded proteins accumulate to form protein aggregates, which is a cause of multiple human pathologies including neurodegeneration, eye disease, and type II diabetes. In cells, protein aggregates can be selectively degraded by autophagy; this process is called aggrephagy. It has been shown that selective autophagy is a potential therapeutic target for the neurodegenerative diseases caused by protein aggregation. However, how the selectivity of this process is achieved has been elusive. Several studies show that the ubiquitin-binding receptors including P62, NBR1, and TAX1BP1 are responsible for the recruitment of autophagic membrane to protein aggregates thus mediating the autophagic clearance of the protein aggregates. However, since these ubiquitin-binding receptors function through recognizing ubiquitin chains, they are usually not specific for aggrephagy as they also function in other types of selective autophagy, like mitophagy, xenophagy, and lysophagy. Specific aggrephagy receptors have been reported in yeast and C. elegans, but it is unclear if there are also specific aggrephagy receptors in mammalian cells. Here, we identified the chaperonin subunit CCT2 as a new type of autophagy receptor regulating the clearance of the aggregation-prone proteins. CCT2 associates with the aggregation-prone proteins independent of cargo ubiquitination and interacts with the autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independent of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or the chaperone-mediated autophagy. Unlike P62, NBR1, or TAX1BP1, CCT2 specifically promotes the autophagic degradation of solid protein aggregates instead of protein condensates with liquidity. Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor via promoting CCT2 monomer formation, which exposes the VLIR motif for ATG8s interaction and therefore, enables its autophagic function. Moreover, we found that multiple other chaperone proteins could promote the autophagic clearance of protein aggregates, which indicates a new role of chaperones in preventing protein aggregates accumulation and maintaining the proteostasis.In summary, this work identifies CCT2 as an aggrephagy receptor for the clearance of solid protein aggregates, and provides new insight into the treatment of multiple human pathologies caused by protein aggregation.
