Department of Biomolecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University (TMDU) (Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Nat Commun. 2024 Oct 29;15(1):9347. doi: 10.1038/s41467-024-53558-x.
Peroxisomes are organelles that are central to lipid metabolism and chemical detoxification. Despite advances in our understanding of peroxisome biogenesis, the mechanisms maintaining peroxisomal membrane proteins remain to be fully elucidated. We show here that mammalian FAF2/UBXD8, a membrane-associated cofactor of p97/VCP, maintains peroxisomal homeostasis by modulating the turnover of peroxisomal membrane proteins such as PMP70. In FAF2-deficient cells, PMP70 accumulation recruits the autophagy adaptor OPTN (Optineurin) to peroxisomes and promotes their autophagic clearance (pexophagy). Pexophagy is also induced by p97/VCP inhibition. FAF2 functions together with p97/VCP to negatively regulate pexophagy rather than as a factor for peroxisome biogenesis. Our results strongly suggest that p97/VCP-mediated extraction of ubiquitylated peroxisomal membrane proteins (e.g., PMP70) prevents peroxisomes from inducing nonessential autophagy under steady state conditions. These findings provide insight into molecular mechanisms underlying the regulation of peroxisomal integrity by p97/VCP and its associated cofactors.
过氧化物酶体是参与脂质代谢和化学解毒的细胞器。尽管我们对过氧化物酶体生物发生的理解取得了进展，但维持过氧化物酶体膜蛋白的机制仍有待充分阐明。我们在这里表明，哺乳动物 FAF2/UBXD8 是 p97/VCP 的膜相关辅助因子，通过调节过氧化物酶体膜蛋白（如 PMP70）的周转率来维持过氧化物酶体的稳态。在 FAF2 缺陷细胞中，PMP70 的积累会招募自噬衔接蛋白 OPTN（Optineurin）到过氧化物酶体，并促进其自噬清除（pexophagy）。p97/VCP 的抑制也会诱导 pexophagy。FAF2 与 p97/VCP 一起负调控 pexophagy，而不是作为过氧化物酶体生物发生的因素。我们的结果强烈表明，p97/VCP 介导的泛素化过氧化物酶体膜蛋白（如 PMP70）的提取可防止过氧化物酶体在稳态条件下诱导非必需的自噬。这些发现为 p97/VCP 及其相关辅助因子调节过氧化物酶体完整性的分子机制提供了深入了解。
