%0 Journal Article
%A Bueno Arribas, Miranda
%A Blanca, Irene
%A Cruz Cuevas, Celia
%A Escalante, Ricardo
%A Navas Hernández, María Ángeles
%A Vincent, Olivier
%T A conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration
%D 2021
%@ 0964-6906
%U https://hdl.handle.net/20.500.14352/91411
%X PROPPINs are phosphoinositide-binding β-propeller proteins that mediate membrane recruitment of other proteins and areinvolved in different membrane remodeling processes. The main role of PROPPINs is their function in autophagy, where theyact at different steps in phagophore formation. The human PROPPIN WIPI4 (WDR45) forms a complex with ATG2 involved inphagophore elongation, and mutations in this gene cause β-propeller protein-associated neurodegeneration (BPAN). Theyeast functional counterpart of WIPI4 is Atg18, although its closest sequence homolog is another member of the PROPPINfamily, 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 thepre-autophagosomal structure (PAS) upon autophagy induction. We further show that Hsv2 drives the recruitment of Atg2to endosomes while Atg2 mediates Hsv2 recruitment to the PAS. HSV2 overexpression results in mis-sorting and secretion ofcarboxypeptidase CPY, suggesting that the endosomal function of this protein is related to the endosome-to-Golgi recyclingpathway. Furthermore, we show that the Atg2 binding site is conserved in Hsv2 and WIPI4 but not in Atg18. Notably, twoWIPI4 residues involved in ATG2 binding are mutated in patients with BPAN, and there is a correlation between theinhibitory effect of these mutations on ATG2 binding and the severity of the disease
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