School of Life Sciences, Peking University, Beijing, China.
National Institute of Biological Sciences, Beijing, China.
EMBO Rep. 2022 Oct 6;23(10):e54859. doi: 10.15252/embr.202254859. Epub 2022 Aug 18.
The hexameric AAA-ATPase valosin-containing protein (VCP) is essential for mitochondrial protein quality control. How VCP is recruited to mammalian mitochondria remains obscure. Here we report that UBXD8, an ER- and lipid droplet-localized VCP adaptor, also localizes to mitochondria and locally recruits VCP. UBXD8 associates with mitochondrial and ER ubiquitin E3 ligases and targets their substrates for degradation. Remarkably, both mitochondria- and ER-localized UBXD8 can degrade mitochondrial and ER substrates in cis and in trans. UBXD8 also associates with the TOM complex but is dispensable for translocation-associated degradation. UBXD8 knockout impairs the degradation of the pro-survival protein Mcl1 but surprisingly sensitizes cells to apoptosis and mitochondrial stresses. UBXD8 knockout also hyperactivates mitophagy. We identify pro-apoptotic BH3-only proteins Noxa, Bik, and Bnip3 as novel UBXD8 substrates and determine that UBXD8 inhibits apoptosis via degrading Noxa and restrains mitophagy via degrading Bnip3. Collectively, our characterizations reveal UBXD8 as the major mitochondrial adaptor of VCP and unveil its role in apoptosis and mitophagy regulation.
六聚体 AAA-ATP 酶包含素蛋白（VCP）对于线粒体蛋白质量控制至关重要。VCP 如何被招募到哺乳动物线粒体仍然不清楚。在这里，我们报告 ER 和脂滴定位的 VCP 衔接蛋白 UBXD8 也定位于线粒体并局部招募 VCP。UBXD8 与线粒体和 ER 泛素 E3 连接酶结合，并将其底物靶向降解。值得注意的是，线粒体和 ER 定位的 UBXD8 都可以顺式和反式降解线粒体和 ER 底物。UBXD8 还与 TOM 复合物结合，但对于易位相关降解是可有可无的。UBXD8 敲除会损害促生存蛋白 Mcl1 的降解，但出人意料的是会使细胞对细胞凋亡和线粒体应激敏感。UBXD8 敲除还会过度激活线粒体自噬。我们鉴定出促凋亡 BH3 仅蛋白 Noxa、Bik 和 Bnip3 为新型 UBXD8 底物，并确定 UBXD8 通过降解 Noxa 抑制细胞凋亡，并通过降解 Bnip3 抑制线粒体自噬。总的来说，我们的研究揭示了 UBXD8 作为 VCP 的主要线粒体衔接蛋白及其在细胞凋亡和线粒体自噬调节中的作用。
