Department of Pediatrics, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):684-694. doi: 10.1016/j.bbamcr.2018.02.006. Epub 2018 Feb 19.
MOAP-1 is a pro-apoptotic tumor suppressor molecule with a growing set of known interacting partners. We have demonstrated that during death receptor-dependent apoptosis, MOAP-1 is recruited to TNF-R1 or TRAIL-R1, followed by RASSF1A and Bax association. MOAP-1/Bax association promotes Bax conformational change resulting in the translocation of Bax into the mitochondrial membrane, mitochondrial membrane insertion and dysregulation resulting in several hallmark events that execute apoptosis. Although a role in apoptosis is established, it is currently unknown how MOAP-1 is regulated and how it links to Bax to promote apoptosis. In this study, we demonstrate robust association with RACK1, a versatile scaffolding protein that responds to activation of protein kinase C. Furthermore, we can demonstrate that RACK1 functions to bring the E3 ligase, TRAF2, to MOAP-1 in order to undergo a K63-dependent ubiquitination. Furthermore, RACK1 associates with MOAP-1 via electrostatic associations similar to those observed between MOAP-1/RASSF1A and MOAP-1/TNF-R1. These events illustrate the complex nature of MOAP-1 regulation and characterizes the important role of the scaffolding protein, RACK1, in influencing MOAP-1 biology.
MOAP-1 是一种促凋亡的肿瘤抑制分子，其已知的相互作用伙伴越来越多。我们已经证明，在死亡受体依赖性细胞凋亡过程中，MOAP-1 被募集到 TNF-R1 或 TRAIL-R1，随后与 RASSF1A 和 Bax 结合。MOAP-1/Bax 结合促进 Bax 构象变化，导致 Bax 转位到线粒体膜，线粒体膜插入和失调导致执行细胞凋亡的几个标志性事件。尽管已经确定了它在细胞凋亡中的作用，但目前尚不清楚 MOAP-1 是如何被调节的，以及它如何与 Bax 结合来促进细胞凋亡。在这项研究中，我们证明了与 RACK1 的强烈关联，RACK1 是一种多功能支架蛋白，对蛋白激酶 C 的激活有反应。此外，我们可以证明 RACK1 的功能是将 E3 连接酶 TRAF2 带到 MOAP-1 上，以进行 K63 依赖性泛素化。此外，RACK1 通过静电相互作用与 MOAP-1 结合，类似于观察到的 MOAP-1/RASSF1A 和 MOAP-1/TNF-R1 之间的相互作用。这些事件说明了 MOAP-1 调节的复杂性，并说明了支架蛋白 RACK1 在影响 MOAP-1 生物学方面的重要作用。
