2024年新着論文 55　細胞情報学分野から論文が発表されました

AAA+ ATPase chaperone p97/VCP^FAF2 governs basal pexophagy

Nat Commun. 2024 Oct 29;15(1):9347. doi: 10.1038/s41467-024-53558-x.

Authors

Fumika Koyano¹, Koji Yamano², Tomoyuki Hoshina², Hidetaka Kosako³, Yukio Fujiki^4 5, Keiji Tanaka⁶, Noriyuki Matsuda⁷

Affiliations

¹ 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. koyano-fm.biom@tmd.ac.jp.
² 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.
³ 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.
⁴ Medical Institute of Bioregulation, Institute of Rheological Functions of Food-Kyushu University Collaboration Program, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
⁵ Institute for Advanced Study, Kyushu University, Fukuoka, 816-8580, Japan.
⁶ Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan.
⁷ 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. nr-matsuda.biom@tmd.ac.jp.

Abstract

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^FAF2-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.

Conflict of interest statement

The authors declare no competing interests.

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