AAA+ ATPase chaperone p97/VCPFAF2 governs basal pexophagy

Fumika Koyano (), Koji Yamano, Tomoyuki Hoshina, Hidetaka Kosako, Yukio Fujiki, Keiji Tanaka and Noriyuki Matsuda ()
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Fumika Koyano: Institute of Science Tokyo)
Koji Yamano: Institute of Science Tokyo)
Tomoyuki Hoshina: Institute of Science Tokyo)
Hidetaka Kosako: Tokushima University
Yukio Fujiki: Kyushu University
Keiji Tanaka: Tokyo Metropolitan Institute of Medical Science
Noriyuki Matsuda: Institute of Science Tokyo)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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/VCPFAF2-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.

Date: 2024
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DOI: 10.1038/s41467-024-53558-x

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