REHS program, San Diego Supercomputer Center, University of California, San Diego, CA, USA.
San Diego Supercomputer Center, University of California, San Diego, CA, USA.
Acta Myol. 2022 Jun 30;41(2):59-75. doi: 10.36185/2532-1900-071. eCollection 2022 Jun.
Bcl2-associated athanogene 3 (BAG3) is a multifunctional cochaperone responsible for protein quality control within cells. BAG3 interacts with chaperones HSPB8 and Hsp70 to transport misfolded proteins to the Microtubule Organizing Center (MTOC) and degrade them in autophagosomes in a process known as Chaperone Assisted Selective Autophagy (CASA). Mutations in the second conserved IPV motif of BAG3 are known to cause Dilated Cardiomyopathy (DCM) by inhibiting adequate removal of non-native proteins. The proline 209 to leucine (P209L) BAG3 mutant in particular causes the aggregation of BAG3 and misfolded proteins as well as the sequestration of essential chaperones. The exact mechanisms of protein aggregation in DCM are unknown. However, the similar presence of insoluble protein aggregates in Charcot-Marie-Tooth disease type 2 (CMT2) induced by the proline 182 to leucine (P182L) HSPB1 mutant points to a possible avenue for future research: IPV motif. In this review, we summarize the molecular mechanisms of CASA and the currently known pathological effects of mutated BAG3 in DCM. Additionally, we will provide insight on the importance of the IPV motif in protein aggregation by analyzing a potential association between DCM and CMT2.
Bcl2 相关抗凋亡基因 3（BAG3）是一种多功能共伴侣，负责细胞内的蛋白质质量控制。BAG3 与伴侣 HSPB8 和 Hsp70 相互作用，将错误折叠的蛋白质运输到微管组织中心（MTOC），并在自噬体中降解它们，这个过程称为伴侣辅助选择性自噬（CASA）。BAG3 第二个保守的 IPV 基序中的突变已知通过抑制非天然蛋白质的适当去除而导致扩张型心肌病（DCM）。特别是 BAG3 的脯氨酸 209 到亮氨酸（P209L）突变体导致 BAG3 和错误折叠的蛋白质聚集以及必需伴侣的隔离。DCM 中蛋白质聚集的确切机制尚不清楚。然而，由脯氨酸 182 到亮氨酸（P182L）HSPB1 突变引起的 Charcot-Marie-Tooth 病 2 型（CMT2）中存在不溶性蛋白质聚集体的相似性表明了未来研究的一个可能途径：IPV 基序。在这篇综述中，我们总结了 CASA 的分子机制以及突变的 BAG3 在 DCM 中的已知病理作用。此外，我们将通过分析 DCM 和 CMT2 之间的潜在关联，提供关于 IPV 基序在蛋白质聚集中的重要性的见解。
