PKM2 compensates for proteasome dysfunction by mediating the formation of the CHIP‐HSP70‐BAG3 complex and the aggregation of ubiquitinated proteins
PKM2 compensates for proteasome dysfunction by mediating the formation of the CHIP‐HSP70‐BAG3 complex and the aggregation of ubiquitinated proteins
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DOI：
10.1096/fj.202101342rr
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发表时间：
2021-12
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影响因子：
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通讯作者：
Chenliang Zhang;Qiu-lin Tang;Hongwei Xia;Huanji Xu;Feng Bi
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作者：
Chenliang Zhang;Qiu-lin Tang;Hongwei Xia;Huanji Xu;Feng Bi
蛋白质的聚集和降解通过自噬(Aggrephagy)是细胞在蛋白酶体功能障碍时去除错误折叠的多肽的主要策略。由热休克蛋白70(Hsp70)、热休克蛋白70/Hsp90相互作用蛋白的辅伴侣泛素连接酶羧基末端(ChIP)和共伴侣蛋白Bcl2相关基因3(BAG3)组成的功能蛋白复合体与蛋白质聚集的激活有关。然而，关于该复合体在蛋白质降解中的作用机制的数据仍然很少。在此，我们报道了在蛋白酶体应激下，丙酮酸激酶M2亚型(PKM2)促进泛素化蛋白的聚集，其敲除或敲除加剧了细胞对蛋白酶体抑制剂的敏感性。此外，在蛋白酶体被抑制后，PKM2促进BAG3与CHIP和HSP70的相互作用。有趣的是，在PKM2基因敲除细胞中功能缺失突变体的重新表达表明，PKM2在这一过程中的调节功能不依赖于糖酵解酶或蛋白激酶的活性。综上所述，这些发现表明，PKM2介导了CHIP-HSP70-BAG3蛋白复合体的形成，并促进了泛素化的错误折叠蛋白的聚集，从而补偿了细胞中的蛋白酶体应激。
Protein aggregation and degradation via autophagy (aggrephagy) are major strategies adopted by cells to remove misfolded polypeptides when there is proteasome dysfunction. The functional protein complex consisting of heat shock protein 70 (Hsp70), cochaperone ubiquitin ligase carboxyl‐terminal of Hsp70/Hsp90 interacting protein (CHIP), and co‐chaperone Bcl‐2‐associated athanogene 3 (BAG3) has been associated with the activation of protein aggregation. However, data on the mechanisms of action of the complex in the protein degradation remains scant. Here, we report that upon proteasome stress, the M2 isoform of pyruvate kinase (PKM2) promotes the aggregation of ubiquitinated proteins and its knockout or knockdown aggravates the sensitivity of cells to proteasome inhibitors. Besides, following proteasome inhibition, PKM2 promotes the interaction of BAG3 with CHIP and HSP70. Interestingly, re‐expression of loss‐of‐function mutants in PKM2‐knockout cells showed that the regulatory function of PKM2 in this progress does not depend on the activity of glycolytic enzymes or protein kinases. Taken together, these findings demonstrate that PKM2 mediates the formation of the CHIP‐HSP70‐BAG3 protein complex and promotes the aggregation of ubiquitinated misfolded proteins, thus compensating for proteasome stress in cells.