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J. Biol. Chem., Vol. 277, Issue 48, 46785-46790, November 29, 2002

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PIKfyve Kinase and SKD1 AAA ATPase Define Distinct Endocytic Compartments
ONLY PIKfyve EXPRESSION INHIBITS THE CELL-VACUOLATING ACTIVITY OF HELICOBACTER PYLORI VacA TOXIN^*

Ognian C. Ikonomov, Diego Sbrissa, Tamotsu Yoshimori^§, Timothy L. Cover^¶, and Assia Shisheva

From the  Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201, the ^§ Department of Cell Genetics, National Institute of Genetics, Yata 1111 Mishima, Shizuoka-ken, Japan, and the ^¶ Department of Medicine and Department of Microbiology and Immunology, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee 37232

The mammalian phosphatidylinositol (PtdIns)- 5-P/PtdIns-3,5-P₂-producing kinase PIKfyve and AAA ATPase SKD1, as their yeast counterparts, are implicated in the formation and function of multivesicular bodies/late endosomes. Point mutations inhibiting the enzyme activities convert PIKfyve and SKD1 into dominant-negative mutants (PIKfyve^K1831E and SKD1^E235Q), whose expression in cells of kidney origin induces a vacuolation phenotype. This phenotype closely resembles the changes in late endosomal-lysosomal morphology that occur following cell exposure to the vacuolating cytotoxin (VacA) from Helicobacter pylori. Here we have examined the possible functional relationship between PIKfyve and SKD1 as well as the role of these enzymes in the molecular mechanism of VacA-induced intracellular vacuolation. When co-expressed in COS cells, PIKfyve^WT reduced SKD1^E235Qdependent vacuole formation, whereas SKD1^WT did not alter the vacuolation induced by PIKfyve^K1831E. In addition, SKD1^E235Q disrupted the normal distribution of PIKfyve^WT. Expression of PIKfyve^WT in COS and HEK293 cells inhibited vacuolation induced by subsequent intoxication with VacA, and microinjection of the PIKfyve lipid product PtdIns-3,5-P₂ produced a similar inhibitory effect. In contrast, in COS cells expressing SKD1^WT, VacA induced the formation of characteristic vacuoles with an efficiency similar to that in the control cells. These observations demonstrate that, although PIKfyve and SKD1 are functionally related, only PIKfyve regulates VacA action, and suggest that the inhibition of PIKfyve PtdIns-3,5-P₂-producing activity is a key molecular event in VacA-induced cellular vacuolation.

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