AAA+ ATPase Chaperone P97/VCP Governs Basal Pexophagy

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Oct 30

PMID 39472561

Authors

Fumika Koyano

Koji Yamano

Tomoyuki Hoshina

Hidetaka Kosako

Yukio Fujiki

Keiji Tanaka

Noriyuki Matsuda

Affiliations

Soon will be listed here.

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-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.

Citing Articles

Pexophagy and Oxidative Stress: Focus on Peroxisomal Proteins and Reactive Oxygen Species (ROS) Signaling Pathways.

Wei X, Manandhar L, Kim H, Chhetri A, Hwang J, Jang G Antioxidants (Basel). 2025; 14(2).

PMID: 40002313 PMC: 11851658. DOI: 10.3390/antiox14020126.

FAF2 is a bifunctional regulator of peroxisomal homeostasis and saturated lipid responses.

Kim C, Gabriel K, Boone D, Brown M, Oppenheimer K, Kost-Alimova M bioRxiv. 2025; .

PMID: 39763943 PMC: 11702540. DOI: 10.1101/2024.12.12.628015.

References

Huybrechts S, Van Veldhoven P, Brees C, Mannaerts G, Los G, Fransen M . Peroxisome dynamics in cultured mammalian cells. Traffic. 2009; 10(11):1722-33. DOI: 10.1111/j.1600-0854.2009.00970.x. View

Sato Y, Okatsu K, Saeki Y, Yamano K, Matsuda N, Kaiho A . Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30. Nat Struct Mol Biol. 2017; 24(11):911-919. DOI: 10.1038/nsmb.3469. View

Neuber O, Jarosch E, Volkwein C, Walter J, Sommer T . Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat Cell Biol. 2005; 7(10):993-8. DOI: 10.1038/ncb1298. View

Yim W, Yamamoto H, Mizushima N . A pulse-chasable reporter processing assay for mammalian autophagic flux with HaloTag. Elife. 2022; 11. PMC: 9385206. DOI: 10.7554/eLife.78923. View

Schrul B, Kopito R . Peroxin-dependent targeting of a lipid-droplet-destined membrane protein to ER subdomains. Nat Cell Biol. 2016; 18(7):740-51. PMC: 4925261. DOI: 10.1038/ncb3373. View

Yamano K, Wang C, Sarraf S, Munch C, Kikuchi R, Noda N . Endosomal Rab cycles regulate Parkin-mediated mitophagy. Elife. 2018; 7. PMC: 5780041. DOI: 10.7554/eLife.31326. View

Araki K, Nagata K . Protein folding and quality control in the ER. Cold Spring Harb Perspect Biol. 2011; 3(11):a007526. PMC: 3220362. DOI: 10.1101/cshperspect.a007526. View

Koyano F, Yamano K, Kosako H, Kimura Y, Kimura M, Fujiki Y . Parkin-mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes. EMBO Rep. 2019; 20(12):e47728. PMC: 6893362. DOI: 10.15252/embr.201947728. View

Liang J, Martinez A, Lane J, Mayor U, Clague M, Urbe S . USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death. EMBO Rep. 2015; 16(5):618-27. PMC: 4428036. DOI: 10.15252/embr.201439820. View

10.

Sirozh O, Saez-Mas A, Jung B, Sanchez-Burgos L, Zarzuela E, Rodrigo-Perez S . Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates aging in mice. Mol Cell. 2024; 84(8):1527-1540.e7. DOI: 10.1016/j.molcel.2024.02.031. View

11.

Zhang J, Tripathi D, Jing J, Alexander A, Kim J, Powell R . ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat Cell Biol. 2015; 17(10):1259-1269. PMC: 4589490. DOI: 10.1038/ncb3230. View

12.

Liu Y, Yagita Y, Fujiki Y . Assembly of Peroxisomal Membrane Proteins via the Direct Pex19p-Pex3p Pathway. Traffic. 2016; 17(4):433-55. DOI: 10.1111/tra.12376. View

13.

Martensson C, Priesnitz C, Song J, Ellenrieder L, Doan K, Boos F . Mitochondrial protein translocation-associated degradation. Nature. 2019; 569(7758):679-683. DOI: 10.1038/s41586-019-1227-y. View

14.

MATSUZONO Y, Kinoshita N, Tamura S, Shimozawa N, Hamasaki M, Ghaedi K . Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly. Proc Natl Acad Sci U S A. 1999; 96(5):2116-21. PMC: 26746. DOI: 10.1073/pnas.96.5.2116. View

15.

Kimura Y, Fukushi J, Hori S, Matsuda N, Okatsu K, Kakiyama Y . Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system. Genes Cells. 2013; 18(12):1131-43. DOI: 10.1111/gtc.12103. View

16.

Stach L, Freemont P . The AAA+ ATPase p97, a cellular multitool. Biochem J. 2017; 474(17):2953-2976. PMC: 5559722. DOI: 10.1042/BCJ20160783. View

17.

Zheng J, Cao Y, Yang J, Jiang H . UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy. EMBO Rep. 2022; 23(10):e54859. PMC: 9535754. DOI: 10.15252/embr.202254859. View

18.

Kim P, Hailey D, Mullen R, Lippincott-Schwartz J . Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci U S A. 2008; 105(52):20567-74. PMC: 2602605. DOI: 10.1073/pnas.0810611105. View

19.

Schuberth C, Buchberger A . Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat Cell Biol. 2005; 7(10):999-1006. DOI: 10.1038/ncb1299. View

20.

Stolz A, Ernst A, Dikic I . Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014; 16(6):495-501. DOI: 10.1038/ncb2979. View