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Vol. 20, Issue 7, 1937-1948, April 1, 2009

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Vps41 Phosphorylation and the Rab Ypt7 Control the Targeting of the HOPS Complex to Endosome–Vacuole Fusion Sites

Margarita Cabrera^*, Clemens W. Ostrowicz^*, Muriel Mari, Tracy J. LaGrassa^*,, Fulvio Reggiori, and Christian Ungermann^*

*Biochemistry Section, Department of Biology, University of Osnabrück, 49076 Osnabrück, Germany; and Department of Cell Biology and Institute of Biomembranes, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands

Submitted September 17, 2008; Revised January 22, 2009; Accepted January 23, 2009
Monitoring Editor: Jean E. Gruenberg

Membrane fusion depends on multisubunit tethering factors such as the vacuolar HOPS complex. We previously showed that the vacuolar casein kinase Yck3 regulates vacuole biogenesis via phosphorylation of the HOPS subunit Vps41. Here, we link the identified Vps41 phosphorylation site to HOPS function at the endosome–vacuole fusion site. The nonphosphorylated Vps41 mutant (Vps41 S-A) accumulates together with other HOPS subunits on punctate structures proximal to the vacuole that expand in a class E mutant background and that correspond to in vivo fusion sites. Ultrastructural analysis of this mutant confirmed the presence of tubular endosomal structures close to the vacuole. In contrast, Vps41 with a phosphomimetic mutation (Vps41 S-D) is mislocalized and leads to multilobed vacuoles, indicative of a fusion defect. These two phenotypes can be rescued by overproduction of the vacuolar Rab Ypt7, revealing that both Ypt7 and Yck3-mediated phosphorylation modulate the Vps41 localization to the endosome–vacuole junction. Our data suggest that Vps41 phosphorylation fine-tunes the organization of vacuole fusion sites and provide evidence for a fusion "hot spot" on the vacuole limiting membrane.

Present address: Jones Day, 222 East 41st St., New York, NY 10017.

Address correspondence to: Christian Ungermann (christian.ungermann{at}biologie.uni-osnabrueck.de)

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