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

被引:268
作者
Proikas-Cezanne, T
Waddell, S
Gaugel, A
Frickey, T
Lupas, A
Nordheim, A
机构
[1] Univ Tubingen, Inst Cell Biol, Dept Mol Biol, Tubingen, Germany
[2] Univ Massachusetts, Sch Med, Dept Neurobiol, Worcester, MA USA
[3] Max Planck Inst Dev Biol, Tubingen, Germany
[4] Univ Tubingen, Inst Cell Biol, Proteome Ctr Tuebingen, Tubingen, Germany
关键词
WD-repeat; ATG18; WIPI49; tumor; homology modeling; autophagy;
D O I
10.1038/sj.onc.1208331
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Phospho-Inosides (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.
引用
收藏
页码:9314 / 9325
页数:12
相关论文
共 48 条
[1]   Autophagy and the cytoplasm to vacuole targeting pathway both require Aut10p [J].
Barth, H ;
Meiling-Wesse, K ;
Epple, UD ;
Thumm, M .
FEBS LETTERS, 2001, 508 (01) :23-28
[2]   The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes [J].
Blommaart, EFC ;
Krause, U ;
Schellens, JPM ;
VreelingSindelarova, H ;
Meijer, AJ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 243 (1-2) :240-246
[3]   A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells [J].
Chernova, OB ;
Hunyadi, A ;
Malaj, E ;
Pan, HQ ;
Crooks, C ;
Roe, B ;
Cowell, JK .
ONCOGENE, 2001, 20 (38) :5378-5392
[4]  
Cuff JA, 2000, PROTEINS, V40, P502, DOI 10.1002/1097-0134(20000815)40:3<502::AID-PROT170>3.0.CO
[5]  
2-Q
[6]   Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors [J].
Dove, SK ;
Piper, RC ;
McEwen, RK ;
Yu, JW ;
King, MC ;
Hughes, DC ;
Thuring, J ;
Holmes, AB ;
Cooke, FT ;
Michell, RH ;
Parker, PJ ;
Lemmon, MA .
EMBO JOURNAL, 2004, 23 (09) :1922-1933
[7]   Defective autophagy leads to cancer [J].
Edinger, AL ;
Thompson, CB .
CANCER CELL, 2003, 4 (06) :422-424
[8]  
FONG HKW, 1986, P NATL ACAD SCI USA, V83, P2162, DOI 10.1073/pnas.83.7.2162
[9]  
Frickey T, 2004, BIOINFORMATICS
[10]   GRAPH DRAWING BY FORCE-DIRECTED PLACEMENT [J].
FRUCHTERMAN, TMJ ;
REINGOLD, EM .
SOFTWARE-PRACTICE & EXPERIENCE, 1991, 21 (11) :1129-1164