7f69

Structural highlights

Disease

WIPI2_HUMAN The disease is caused by variants affecting the gene represented in this entry.

Function

WIPI2_HUMAN Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:20505359, PubMed:28561066). Involved in an early step of the formation of preautophagosomal structures (PubMed:20505359, PubMed:28561066). Binds and is activated by phosphatidylinositol 3-phosphate (PtdIns3P) forming on membranes of the endoplasmic reticulum upon activation of the upstream ULK1 and PI3 kinases (PubMed:28561066). Mediates ER-isolation membranes contacts by interacting with the ULK1:RB1CC1 complex and PtdIns3P (PubMed:28890335). Once activated, WIPI2 recruits at phagophore assembly sites the ATG12-ATG5-ATG16L1 complex that directly controls the elongation of the nascent autophagosomal membrane (PubMed:20505359, PubMed:28561066).^{[1] [2] [3] [4]} Recruits the ATG12-ATG5-ATG16L1 complex to omegasomes and preautophagosomal structures, resulting in ATG8 family proteins lipidation and starvation-induced autophagy. Isoform 4 is also required for autophagic clearance of pathogenic bacteria. Isoform 4 binds the membrane surrounding Salmonella and recruits the ATG12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.^[5]

References

1. ↑ Polson HE, de Lartigue J, Rigden DJ, Reedijk M, Urbe S, Clague MJ, Tooze SA. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy. 2010 May;6(4):506-22. doi: 10.4161/auto.6.4.11863. Epub 2010 May 16. PMID:20505359 doi:http://dx.doi.org/10.4161/auto.6.4.11863
2. ↑ Bakula D, Muller AJ, Zuleger T, Takacs Z, Franz-Wachtel M, Thost AK, Brigger D, Tschan MP, Frickey T, Robenek H, Macek B, Proikas-Cezanne T. WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nat Commun. 2017 May 31;8:15637. doi: 10.1038/ncomms15637. PMID:28561066 doi:http://dx.doi.org/10.1038/ncomms15637
3. ↑ Zhao YG, Chen Y, Miao G, Zhao H, Qu W, Li D, Wang Z, Liu N, Li L, Chen S, Liu P, Feng D, Zhang H. The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation. Mol Cell. 2017 Sep 21;67(6):974-989.e6. doi: 10.1016/j.molcel.2017.08.005. Epub, 2017 Sep 7. PMID:28890335 doi:http://dx.doi.org/10.1016/j.molcel.2017.08.005
4. ↑ Jelani M, Dooley HC, Gubas A, Mohamoud HSA, Khan MTM, Ali Z, Kang C, Rahim F, Jan A, Vadgama N, Khan MI, Al-Aama JY, Khan A, Tooze SA, Nasir J. A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities. Brain. 2019 May 1;142(5):1242-1254. doi: 10.1093/brain/awz075. PMID:30968111 doi:http://dx.doi.org/10.1093/brain/awz075
5. ↑ Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell. 2014 Jul 17;55(2):238-52. doi: 10.1016/j.molcel.2014.05.021. Epub 2014 , Jun 19. PMID:24954904 doi:http://dx.doi.org/10.1016/j.molcel.2014.05.021