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