A conserved ATG2 binding site in WIPI4 and yeast Hsv2 is disrupted by mutations causing β-propeller protein-associated neurodegeneration
Loading...
Download
Official URL
Full text at PDC
Publication date
2021
Advisors (or tutors)
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford Academic
Citation
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.
Abstract
PROPPINs 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