title: WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy.
abstract: 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)-1alpha (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-1alpha 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.
authors.affiliation: Department of Molecular Biology, Institute for Cell Biology, University of Tuebingen, Auf der Morgenstelle 15, Tuebingen, Germany. tassula.proikas-cezanne@uni-tuebingen.de
authors.forename: Tassula
authors.initials: T
authors.lastname: Proikas-Cezanne
authors.forename: Scott
authors.initials: S
authors.lastname: Waddell
authors.forename: Anja
authors.initials: A
authors.lastname: Gaugel
authors.forename: Tancred
authors.initials: T
authors.lastname: Frickey
authors.forename: Andrei
authors.initials: A
authors.lastname: Lupas
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
mesh_terms: D000595:Amino Acid Sequence; D001343:Autophagy / Q000502:physiology*; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000235:genetics*; D010802:Phylogeny; D011485:Protein Binding; D011987:Receptors, Steroid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013217:Starvation
chemical_list: D009363:Neoplasm Proteins; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase