10.6084/M9.FIGSHARE.19542371
Guang Lu
Guang
Lu
Hayden Weng Siong Tan
Hayden Weng Siong
Tan
Tomas Schmauck-Medina
Tomas
Schmauck-Medina
Liming Wang
Liming
Wang
Jiaqing Chen
Jiaqing
Chen
Yik-Lam Cho
Yik-Lam
Cho
Kelie Chen
Kelie
Chen
Jing-Zi Zhang
Jing-Zi
Zhang
Weifeng He
Weifeng
He
Yihua Wu
Yihua
Wu
Dajing Xia
Dajing
Xia
Jing Zhou
Jing
Zhou
Evandro F. Fang
Evandro F.
Fang
Lei Fang
Lei
Fang
Wei Liu
Wei
Liu
Han-Ming Shen
Han-Ming
Shen
WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP
<p>The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of <i>WIPI2</i> impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and <i>WIPI2</i> depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy.</p> <p><b>Abbreviations:</b> ATG, autophagy related; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide chlorophenylhydrazone; CYCS, cytochrome c, somatic; HSPD1/HSP60, heat shock protein family D (Hsp60) member 1; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NPLOC4, NPL4 homolog, ubiquitin recognition factor; OMM, outer mitochondrial membrane; OPTN, optineurin; PtdIns3P, phosphatidylinositol-3-phosphate; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; UBXN6/UBXD1, UBX domain protein 6; UFD1, ubiquitin recognition factor in ER associated degradation 1; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2</p>
Biochemistry
Cell Biology
Genetics
Molecular Biology
Neuroscience
Physiology
Immunology
Developmental Biology
Cancer
Infectious Diseases
Taylor & Francis
2022
2022-04-07
2023-05-30
Dataset
14679546 Bytes
10.1080/15548627.2022.2052461
CC BY 4.0