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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5308-5317.
Prepublished online as a Blood First Edition Paper on March 6, 2007; DOI 10.1182/blood-2007-01-067363.
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IMMUNOBIOLOGY
Roles of RabGEF1/Rabex-5 domains in regulating Fc RI surface expression and FcRI-dependent responses in mast cells
Janet Kalesnikoff1,
Eon J. Rios1,
Ching-Cheng Chen1,
M. Alejandro Barbieri2,
Mindy Tsai1,
See-Ying Tam1, and
Stephen J. Galli1
1 Department of Pathology, Stanford University School of Medicine, Stanford, CA;
2 Department of Biological Sciences, Florida International University, College of Arts and Sciences, Miami, FL
RabGEF1/Rabex-5, a guanine nucleotide exchange factor (GEF) for the endocytic pathway regulator, Rab5, contains a Vps9 domain, an A20-like zinc finger (ZnF) domain, and a coiled coil domain. To investigate the importance of these domains in regulating receptor internalization and cell activation, we lentivirally delivered RabGEF1 mutants into RabGEF1-deficient (–/–) mast cells and examined Fc RI-dependent responses. Wild-type RabGEF1 expression corrected phenotypic abnormalities in –/– mast cells, including decreased basal FcRI expression, slowed FcRI internalization, elevated IgE + Ag–induced degranulation and IL-6 production, and the decreased ability of –/– cytosol to support endosome fusion. We showed that RabGEF1's ZnF domain has ubiquitin ligase activity. Moreover, the coiled coil domain of RabGEF1 is required for Rabaptin-5 binding and for maintaining basal levels of Rabaptin-5 and surface FcRI. However, mutants lacking either of these domains normalized phenotypic abnormalities in IgE + antigen–activated –/– mast cells. By contrast, correction of these –/– phenotypes required a functional Vps9 domain. Thus, FcRI-mediated mast cell functional activation is dependent on RabGEF1's GEF activity.
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