Department of Cell and Molecular Physiology, Loyola University Chicago, Chicago, Illinois, USA.
Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
J Clin Invest. 2021 Aug 16;131(16). doi: 10.1172/JCI149415.
Bcl2-associated athanogene-3 (BAG3) is expressed ubiquitously in humans, but its levels are highest in the heart, the skeletal muscle, and the central nervous system; it is also elevated in many cancers. BAG3's diverse functions are supported by its multiple protein-protein binding domains, which couple with small and large heat shock proteins, members of the Bcl2 family, other antiapoptotic proteins, and various sarcomere proteins. In the heart, BAG3 inhibits apoptosis, promotes autophagy, couples the β-adrenergic receptor with the L-type Ca2+ channel, and maintains the structure of the sarcomere. In cancer cells, BAG3 binds to and supports an identical array of prosurvival proteins, and it may represent a therapeutic target. However, the development of strategies to block BAG3 function in cancer cells may be challenging, as they are likely to interfere with the essential roles of BAG3 in the heart. In this Review, we present the current knowledge regarding the biology of this complex protein in the heart and in cancer and suggest several therapeutic options.
Bcl2 相关抗凋亡基因 3（BAG3）在人体中广泛表达，但在心脏、骨骼肌和中枢神经系统中表达水平最高；它在许多癌症中也升高。BAG3 的多种功能由其多个蛋白-蛋白结合结构域支持，这些结构域与小分子和大分子量热休克蛋白、Bcl2 家族成员、其他抗凋亡蛋白以及各种肌节蛋白结合。在心脏中，BAG3 抑制细胞凋亡、促进自噬、将β-肾上腺素能受体与 L 型 Ca2+通道偶联，并维持肌节的结构。在癌细胞中，BAG3 与一组相同的生存蛋白结合并支持它们，它可能代表一个治疗靶点。然而，开发阻断癌细胞中 BAG3 功能的策略可能具有挑战性，因为它们可能干扰 BAG3 在心脏中的重要作用。在这篇综述中，我们介绍了该复杂蛋白在心脏和癌症中的生物学特性的最新知识，并提出了几种治疗选择。
