WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy

WD-repeat proteins are regulatory beta-propeller platforms that enable the assembly of multiprotein complexes. Here, we report the functional and bioinformatic analysis of human WD-repeat protein Interacting with PhosphoInosides (WIPI)-1α (WIPI49/Atg18), a member of a novel WD-repeat protein family with autophagic capacity in Saccharomyces cerevisiae and Caenorhabditis elegans, recently identified as phospholipid-binding effectors. Our phylogenetic analysis divides the WIPI protein family into two paralogous groups that fold into 7-bladed beta-propellers. Structural modeling identified two evolutionary conserved interaction sites in WIPI propellers, one of which may bind phospholipids. Human WIPI-1α has LXXLL signature motifs for nuclear receptor interactions and binds androgen and estrogen receptors in vitro. Strikingly, human WIPI genes were found aberrantly expressed in a variety of matched tumor tissues including kidney, pancreatic and skin cancer. We found that endogenous hWIPI-1 protein colocalizes in part with the autophagosomal marker LC3 at punctate cytoplasmic structures in human melanoma cells. In addition, hWIPI-1 accumulated in large vesicular and cup-shaped structures in the cytoplasm when autophagy was induced by amino-acid deprivation. These cytoplasmic formations were blocked by wortmannin, a classic inhibitor of PI-3 kinase-mediated autophagy. Our data suggest that WIPI proteins share an evolutionary conserved function in autophagy and that autophagic capacity may be compromised in human cancers.

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