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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

Oncogene volume 23, pages 9314–9325 (2004)Cite this article

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)-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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Acknowledgements

We are most grateful to Tamotsu Yoshimori for kindly providing the GFP-LC3 construct, and thank Johannes Soeding and Yakov Sergeev for assistance with the hWIPI-1α model. We also thank Malcolm Parker, Frank Gannon, Roland Schuele, Hubert Kalbacher and Birgit Schittek for reagents used in this study. We appreciate initial bioinformatic analysis by Stefan Steigele and Kay Nieselt-Struwe, and expert advice on confocal microscopy by Roland Brock. Initial isolation of hWIPI-1α was part of a postdoctoral fellowship by the Deutsche Forschungsgemeinschaft, Germany to TP-C, conducted at the Marie Curie Research Institute, UK. This work is supported by the Fritz Thyssen Stiftung, Germany, and the Fonds der Chemischen Industrie.

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Authors and Affiliations

  1. Department of Molecular Biology, Institute for Cell Biology, University of Tuebingen, Auf der Morgenstelle 15, Tuebingen, Germany

    Tassula Proikas-Cezanne, Anja Gaugel & Alfred Nordheim

  2. Department of Neurobiology, University of Massachusetts Medical School, Worcester, USA

    Scott Waddell

  3. Max-Planck-Institute for Developmental Biology, Tuebingen, Germany

    Tancred Frickey & Andrei Lupas

  4. Proteome Center Tuebingen, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany

    Alfred Nordheim

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  1. Tassula Proikas-Cezanne
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Correspondence to Tassula Proikas-Cezanne.

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Proikas-Cezanne, T., Waddell, S., Gaugel, A. et al. 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. Oncogene 23, 9314–9325 (2004). https://doi.org/10.1038/sj.onc.1208331

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