A conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration

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dc.contributor.authorBueno Arribas, Miranda
dc.contributor.authorBlanca, Irene
dc.contributor.authorCruz Cuevas, Celia
dc.contributor.authorEscalante, Ricardo
dc.contributor.authorNavas Hernández, María Ángeles
dc.contributor.authorVincent, Olivier
dc.date.accessioned2023-12-18T08:44:07Z
dc.date.available2023-12-18T08:44:07Z
dc.date.issued2021-08-09
dc.description.abstractPROPPINs are phosphoinositide-binding β-propeller proteins that mediate membrane recruitment of other proteins and are involved in different membrane remodeling processes. The main role of PROPPINs is their function in autophagy, where they act at different steps in phagophore formation. The human PROPPIN WIPI4 (WDR45) forms a complex with ATG2 involved in phagophore elongation, and mutations in this gene cause β-propeller protein-associated neurodegeneration (BPAN). The yeast functional counterpart of WIPI4 is Atg18, although its closest sequence homolog is another member of the PROPPIN family, Hsv2, whose function remains largely undefined. Here, we provide evidence that Hsv2, like WIPI4 and Atg18, interacts with Atg2. We show that Hsv2 and a pool of Atg2 colocalize on endosomes under basal conditions and at the pre-autophagosomal structure (PAS) upon autophagy induction. We further show that Hsv2 drives the recruitment of Atg2 to endosomes while Atg2 mediates Hsv2 recruitment to the PAS. HSV2 overexpression results in mis-sorting and secretion of carboxypeptidase CPY, suggesting that the endosomal function of this protein is related to the endosome-to-Golgi recycling pathway. Furthermore, we show that the Atg2 binding site is conserved in Hsv2 and WIPI4 but not in Atg18. Notably, two WIPI4 residues involved in ATG2 binding are mutated in patients with BPAN, and there is a correlation between the inhibitory effect of these mutations on ATG2 binding and the severity of the disease
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades
dc.description.statuspub
dc.identifier.citationBueno-Arribas M, Blanca I, Cruz-Cuevas C, Escalante R, Navas MA, Vincent O. A conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration. Hum Mol Genet. 2021 Dec 17;31(1):111-121.
dc.identifier.doi10.1093/hmg/ddab225
dc.identifier.essn1460-2083
dc.identifier.issn0964-6906
dc.identifier.urihttps://hdl.handle.net/20.500.14352/91411
dc.issue.number1
dc.journal.titleHuman Molecular Genetics
dc.language.isoeng
dc.page.final121
dc.page.initial111
dc.publisherOxford Academic
dc.relation.projectIDPGC2018-093604-B-I00
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu577.1
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmCiencias
dc.subject.unesco24 Ciencias de la Vida
dc.titleA conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number31
dspace.entity.typePublication
relation.isAuthorOfPublication2996f3da-ebc0-41be-98c4-32a67724a052
relation.isAuthorOfPublication.latestForDiscovery2996f3da-ebc0-41be-98c4-32a67724a052
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