RT Journal Article
T1 A conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration
A1 Bueno Arribas, Miranda
A1 Blanca, Irene
A1 Cruz Cuevas, Celia
A1 Escalante, Ricardo
A1 Navas Hernández, María Ángeles
A1 Vincent, Olivier
AB 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
PB Oxford Academic
SN 0964-6906
YR 2021
FD 2021-08-09
LK https://hdl.handle.net/20.500.14352/91411
UL https://hdl.handle.net/20.500.14352/91411
LA eng
NO Bueno-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.
NO Ministerio de Ciencia, Innovación y Universidades
DS Docta Complutense
RD 20 ago 2024