MCL-1 BH3 螺旋与 VLCAD 之间的非经典相互作用对长链脂肪酸氧化的动态调节
Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD.
机构信息
Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Mol Cell. 2018 Mar 1;69(5):729-743.e7. doi: 10.1016/j.molcel.2018.02.005.
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1 alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.
MCL-1 是一种 BCL-2 家族蛋白，参与人类癌症的发生和化疗耐药。与其他抗凋亡同源物不同，Mcl-1 的缺失会产生深远的生理后果，表明其在稳态中具有更广泛的作用。我们报告称，MCL-1 的 BCL-2 同源结构域 3（BH3）α 螺旋可以直接与非常长链酰基辅酶 A 脱氢酶（VLCAD）结合，VLCAD 是线粒体脂肪酸 β-氧化（FAO）途径的关键酶。蛋白质组学分析证实，MCL-1 的线粒体基质同工型（MCL-1）与 VLCAD 相互作用。Mcl-1 的缺失，或单独消除 MCL-1，会选择性地下调长链 FAO，导致在营养物质缺乏时，该途径的通量增加。血清剥夺时 MCL-1 的短暂升高，棕榈酸滴定时 MCL-1 BH3/VLCAD 相互作用的显著增加，以及 MCL-1 BH3 α 螺旋对酶活性的直接调节，都与动态调节一致。因此，MCL-1 BH3 与 VLCAD 的相互作用揭示了 MCL-1 在脂质代谢调节中具有可分离的、获得功能的作用。
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