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Published 9 July 2001. doi:10.1083/jcb.200102142
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© The Rockefeller University Press, 0021-9525/2001/7/109 $5.00
The Journal of Cell Biology, Volume 154, Number 1, July 9, 2001 109-122

Article

Human Vam6p promotes lysosome clustering and fusion in vivo



Steve Caplan1, Lisa M. Hartnell1, Rubén C. Aguilar1, Naava Naslavsky2 and Juan S. Bonifacino1

1 Cell Biology and Metabolism Branch at the National Institute of Child Health and Human Development, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892
2 Laboratory of Cell Biology at the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Juan S. Bonifacino, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T/Room 101, National Institutes of Health, Bethesda, MD 20892. Tel.: (301) 496-6368. Fax: (301) 402-0078. E-mail: juan{at}helix.nih.gov

Regulated fusion of mammalian lysosomes is critical to their ability to acquire both internalized and biosynthetic materials. Here, we report the identification of a novel human protein, hVam6p, that promotes lysosome clustering and fusion in vivo. Although hVam6p exhibits homology to the Saccharomyces cerevisiae vacuolar protein sorting gene product Vam6p/Vps39p, the presence of a citron homology (CNH) domain at the NH2 terminus is unique to the human protein. Overexpression of hVam6p results in massive clustering and fusion of lysosomes and late endosomes into large (2–3 µm) juxtanuclear structures. This effect is reminiscent of that caused by expression of a constitutively activated Rab7. However, hVam6p exerts its effect even in the presence of a dominant-negative Rab7, suggesting that it functions either downstream of, or in parallel to, Rab7. Data from gradient fractionation, two-hybrid, and coimmunoprecipitation analyses suggest that hVam6p is a homooligomer, and that its self-assembly is mediated by a clathrin heavy chain repeat domain in the middle of the protein. Both the CNH and clathrin heavy chain repeat domains are required for induction of lysosome clustering and fusion. This study implicates hVam6p as a mammalian tethering/docking factor characterized with intrinsic ability to promote lysosome fusion in vivo.

Key Words: lysosome biogenesis; vacuolar protein sorting; vesicle tethering; vesicle docking; lysosome fusion


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