Rafkinase Inhibitor Protein RKIP Negativelv Regulates FcεR1-mediated Mast Cell Activation And Allergic Response

Mast cels are BM-derived hematopoietic cells localized under surface exposed to the external environment,such as the skin,airways,and intestine,functions as essential cells in host defense reactions including immediate hypersensitivity responses and allergic responses.Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in their degranulation and proinflamatory cytokine production,which are key effectors in allergic reaction.RKIP,identified as a RAF-1 binding protein,inhibits MEK phosphorylation and activation.It has been widely accepted that RKIP can regulate cancer cell metastasis.We recently indentified that RKIP positively regulates anti-virus immune response and promotes the development of IBD.RKIP expression has been detected in all mammalian tissues,such as brain,liver,stomach,spleen and muscle of human,as well as mast cell.However,the fimction of RKIP in allergic response remains unknown.In this study,we first identified RKIP as an inhibitory modulator for FcεRI-mediated mast cell activation by targeting PI3K subunit p85α.RKIP deficiency significantly exacerbated mast cell-mediated anaphylactic response and allergic asthma in mice.RKIP KO mast cells showed hyper-responsiveness to FcεRI stimulation,which was evidenced by enhanced cytokine production,degranulation,and elevated activation of downstream signaling pathway.Mechanically,we found RKIP negatively mediates PI3K/Akt/NF-KB axis signaling activation through interaction with PI3K subunit p85a.Mechanically,RKIP conpetes with Gab2 to interact with p85α and suppresses the activation of PI3K.Taken together,our findings establish RKIP as a key suppressor of mast cell-mediated anaphylactic response and indicate that the development of RKIP-peptide-mimicking drugs may be a new and feasible approache for allergic asthma treatment.