Phosphorylation of SNAP-23 by IkappaB kinase 2 regulates mast cell degranulation.
Mast cells are known to play a pivotal role in allergic diseases. Cross-linking of the high-affinity receptor for IgE (FcepsilonRI) leads to degranulation and allergic inflammation; however, the regulatory mechanisms of IgE-dependent exocytosis remain unknown. We show here that IkappaB kinase (IKK) 2 in mast cells plays critical roles in IgE-mediated anaphylaxis in vivo, and IgE-mediated degranulation in vitro, in an NF-kB-independent manner. Upon FcvarepsilonRI stimulation, IKK2 phosphorylates SNAP-23, the target membrane soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor (SNARE), and ectopic expression of a phospho-mimetic mutant of SNAP-23 partially rescued the impaired IgE-mediated degranulation in IKK2-deficient mast cells. These results suggest that IKK2 phosphorylation of SNAP-23 leads to degranulation and anaphylactic reactions. While this reaction is NF-kB-independent, we additionally show that IKK2 also regulates late-phase allergic reactions promoted by the release of proinflammatory cytokines in an NF-kB-dependent manner. The findings suggest that IKK2 is a central player in allergic reactions.
Suzuki
Kotaro
K
Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Verma
Inder M
IM
D000707:Anaphylaxis / Q000276:immunology; D000818:Animals; D015550:Cell Degranulation; D051550:I-kappa B Kinase / Q000378:metabolism*; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000166:cytology* / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D050766:Qb-SNARE Proteins / Q000378:metabolism*; D050767:Qc-SNARE Proteins / Q000378:metabolism*
D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C107017:Snap23 protein, mouse; D007073:Immunoglobulin E; D051550:I-kappa B Kinase