Autophagy
·
2022
·
IF 13.391
Guang Lu,Hayden Weng Siong Tan,Tomas Schmauck-Medina,Liming Wang,Jiaqing Chen,Yik-Lam Cho,Kelie Chen,Jing-Zi Zhang,Weifeng He,Yihua Wu,Dajing Xia,Jing Zhou,Evandro F. Fang,Lei Fang,Wei Liu,Han-Ming Shen
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 WIPI2 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 WIPI2 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.Abbreviations: 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
研究领域:
细胞生物学
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分子生物学
·
自噬
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 8
·4493
·
IF 4.9
Jiuge Tang,Dongmei Fang,Jialing Zhong,Min Li
Canonical autophagy is an evolutionarily conserved process that forms double-membrane structures and mediates the degradation of long-lived proteins (LLPs). Noncanonical autophagy (NCA) is an important alternative pathway involving the formation of microtubule-associated protein 1 light chain 3 (LC3)-positive structures that are independent of partial core autophagy proteins. NCA has been defined by the conjugation of ATG8s to single membranes (CASM). During canonical autophagy and NCA/CASM, LC3 undergoes a lipidation modification, and ATG16L1 is a crucial protein in this process. Previous studies have reported that the WDR domain of ATG16L1 is not necessary for canonical autophagy. However, our study found that WDR domain deficiency significantly impaired LLP degradation in basal conditions and slowed down LC3-II accumulation in canonical autophagy. We further demonstrated that the observed effect was due to a reduced interaction between ATG16L1 and FIP200/WIPI2, without affecting lysosome function or fusion. Furthermore, we also found that the WDR domain of ATG16L1 is crucial for chemical-induced NCA/CASM. The results showed that removing the WDR domain or introducing the K490A mutation in ATG16L1 significantly inhibited the NCA/CASM, which interrupted the V-ATPase-ATG16L1 axis. In conclusion, this study highlights the significance of the WDR domain of ATG16L1 for both canonical autophagy and NCA functions, improving our understanding of its role in autophagy.
研究领域:
细胞生物学
·
分子生物学
·
自噬
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Xue Sun,Haohao Cui,Jingfan Li,Boyuan An,Ruixing Liu,Zhihua Guo,Dandan Chu,Xingchen Geng,Bingbing Cui,Lei Zhu,Jingguo Li,Zhanrong Li
Subconjunctival fibrosis (SCF) is a common and refractory eye disease that is a serious threat to vision. The severe side effects of existing drugs and low drug bioavailability due to the ocular barrier are major challenges in SCF treatment. Hence, there is an urgent need to explore safer and more effective strategies for administering anti-SCF drugs. Herein, an injectable and adaptable hydrogel system containing the antifibrotic drug rapamycin was fabricated to address this complex need. This system possesses moderate mechanical properties, self-healing and shape-adaptive capabilities, injectability, and biosafety. It is designed to promote autophagy by modulating the PI3K/AKT/mTOR/WIPI2 pathway, thereby inhibiting SCF. In vivo experiments utilizing a rat subconjunctival injury model indicated that in situ administration of this hydrogel system effectively inhibited SCF. This system constitutes a promising method for promoting autophagy to protect against SCF, which will foster its widespread application for other fibrotic diseases.
研究领域:
眼科学
·
药学
·
生物材料
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）