错误折叠蛋白的聚集和自噬途径降解是细胞应对蛋白酶体活力下降的主要保护机制，也是肿瘤细胞对蛋白酶体抑制剂耐药的主要原因。虽然已经证实E3泛素连接酶CHIP和分子伴侣HSP70、分子伴侣结合蛋白BAG3形成的复合体是错误折叠蛋白聚集及自噬途径降解的关键，但是CHIP-HSP70-BAG3复合体形成的分子机制并不清楚。我们前期研究发现肿瘤代谢酶PKM2可以作为蛋白酶体活力感应分子，通过非激酶活性调控蛋白酶体抑制时CHIP-HSP70-BAG3复合体的形成以及错误折叠蛋白的聚集。本项目将研究PKM2应答蛋白酶体应激和调控CHIP-HSP70-BAG3复合体介导的错误折叠蛋白聚集与清除的分子机制，同时在体内探索联合靶向抑制PKM2和蛋白酶体来治疗肿瘤的新策略，进而为我们认识错误折叠蛋白聚集和清除的分子机制提供新的理论依据，并为蛋白酶体抑制剂相关的肿瘤治疗提供新的联合治疗策略。

The aggregation of misfolded proteins is critical for efficient clearance of cytotoxic misfolded proteins through autophagy system during proteasome inhibition and plays a cytoprotective role in cancer cells treated with proteasome inhibitor. Despite the well-established role of the complex formation of E3 ubiquitin ligase CHIP, heat shock protein HSP70 and co-chaperone protein BAG3 in misfolded proteins aggregation and selective degradation by autophagy, how CHIP-HSP70 binds BAG3 in response to proteasome inhibition is poorly understood. Our previous study found that PKM2 predominantly expressed in tumor cells and seemed to be important for cancer cell metabolic adaptation is, as a non-kinase role, involved in the regulation of aggregation of misfolded proteins under proteasome inhibition that induced the PKM2 interaction with CHIP-HSP70-BAG3 complex. In this study, we will investigate the molecular mechanism of PKM2-mediated the formation of CHIP-HSP70-BAG3 complex and misfolded protein aggregation and degradation during proteasome inhibition and the effect of PKM2 on drug sensitivities and tumor xenografts of cancer cells to proteasome inhibitor, in order to further increase our understanding of misfolded protein clearance and develop the treatment of cancer by proteasome inhibitors.