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Vol. 20, Issue 4, 1223-1240, February 15, 2009

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SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Guang-dan Zhu^*, Gloria Salazar, Stephanie A. Zlatic^,, Babar Fiza^*,, Michele M. Doucette^,||, Craig J. Heilman^¶,#, Allan I. Levey^¶,#, Victor Faundez^,,#, and Steven W. L'Hernault^*,,#

Graduate Program in Biochemistry, Cell, and Developmental Biology, Departments of *Biology and Cell Biology, and ^¶Department of Neurology, ^#Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322

Submitted July 16, 2008; Revised December 2, 2008; Accepted December 5, 2008
Monitoring Editor: Sean Munro

Yeast and animal homotypic fusion and vacuole protein sorting (HOPS) complexes contain conserved subunits, but HOPS-mediated traffic in animals might require additional proteins. Here, we demonstrate that SPE-39 homologues, which are found only in animals, are present in RAB5-, RAB7-, and RAB11-positive endosomes where they play a conserved role in lysosomal delivery and probably function via their interaction with the core HOPS complex. Although Caenorhabditis elegans spe-39 mutants were initially identified as having abnormal vesicular biogenesis during spermatogenesis, we show that these mutants also have disrupted processing of endocytosed proteins in oocytes and coelomocytes. C. elegans SPE-39 interacts in vitro with both VPS33A and VPS33B, whereas RNA interference of VPS33B causes spe-39–like spermatogenesis defects. The human SPE-39 orthologue C14orf133 also interacts with VPS33 homologues and both coimmunoprecipitates and cosediments with other HOPS subunits. SPE-39 knockdown in cultured human cells altered the morphology of syntaxin 7-, syntaxin 8-, and syntaxin 13-positive endosomes. These effects occurred concomitantly with delayed mannose 6-phosphate receptor-mediated cathepsin D delivery and degradation of internalized epidermal growth factor receptors. Our findings establish that SPE-39 proteins are a previously unrecognized regulator of lysosomal delivery and that C. elegans spermatogenesis is an experimental system useful for identifying conserved regulators of metazoan lysosomal biogenesis.

Present addresses: University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599;

^|| School of Health Professions, Division of Nutrition, Georgia State University, P.O. Box 3995, Atlanta, GA 30302.

Address correspondence to: Steven W. L'Hernault (bioslh{at}biology.emory.edu) or Victor Faundez (faundez{at}cellbio.emory.edu).

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