Hongbo Hu's Lab
The State Key Laboratory of Biotherapy Si-Chuan University
 
Lyn Kinase Suppresses the Transcriptional Activity of IRF5 in the TLR-MyD88 Pathway to Restrain the

 Innate immune response isessential for host defense. However, hyperactive innate immune  response leads to undesirable inflammationand breakdown of immune tolerance, causing autoimmune diseases. Interferonregulatory factor 5 (IRF5),a critical transcriptional factor, plays animportant role in innate immune response and also contributes to the pathogenesisof systemic lupus erythematosus(SLE).Recent studies have shown that there is agenetic association between lyn and SLE[1,2].Lyn is a non-receptortyrosine kinase that functions in multiple aspects of immune response. DC or Bcell specific deletion of Lyn results in the development of SLE-like symptoms,which are abrogated by deletion of MyD88 in both cases[3,4]. However,the mechanism of how Lyn works in TLR-MyD88 pathway remains unknown.

 In the current study, the authorsfind that Lyn is a negative regulator of IRF5 during screening IRF5 bindingkinase. Lyn is recruited by MyD88 to form a Lyn-MyD88-IRF5 complex. Theinteraction between Lyn and IRF5 results in selective suppression of K63ubiquitination (by TRAF6) and phosphorylation (by IKKβ) of IRF5,thus inhibitsthe activity of IRF5.However, this inhibition doesn’t rely on the kinaseactivity of Lyn, or has no effect on NF-κB signaling, downstream ofMyD88.Mono-allelic or bia-allelic deletion of IRF5 is sufficient to amelioratethe hyperprodution of cytokines in TLR-stimulated Lyn-deficient DCs and thedevelopment of SLE-like symptoms in Lyn deficient mice. Although Lyn has beenreported to suppress innate immune signaling along the TLR-MyD88 in DCs and Bcells[5],constitutive activation of IRF5 in vivo is detected only infreshly isolated Lyn deficient DCs but not B cells. Further investigation isrequired to more clearly define the physiological role of IRF5 in Lyn deficientB cells.


References:

1.    Deng, Y., and Tsao, B.P.(2010). Genetic susceptibility to systemic lupus erythematosus in the genomicera. Nat. Rev. Rheumatol. 6, 683–692.

2.    Mohan, C., and Putterman,C. (2015). Genetics and pathogenesis of systemic lupus erythematosus and lupusnephritis. Nat. Rev. Nephrol. 11, 329–341.

3.    Gutierrez, T., Halcomb,K.E., Coughran, A.J., Li, Q.Z., and Satterthwaite, A.B.(2010). Separatecheckpoints regulate splenic plasma cell accumulation and IgG autoantibodyproduction in Lyn-deficient mice. Eur. J. Immunol. 40,1897–1905.

4.    Hibbs, M.L., Tarlinton,D.M., Armes, J., Grail, D., Hodgson, G., Maglitto, R.Stacker, S.A., and Dunn,A.R. (1995). Multiple defects in the immune system of Lyn-deficient mice,culminating in autoimmune disease. Cell 83, 301–311.

5.    Jabara, H.H., McDonald,D.R., Janssen, E., Massaad, M.J., Ramesh, N.Borzutzky, A., Rauter, I., Benson,H., Schneider, L., Baxi, S., et al. (2012).DOCK8 functions as an adaptor thatlinks TLR-MyD88 signaling to B cell activation.Nat. Immunol. 13, 612–620.



By Jun



 ORIGINAL RESEARCH PAPER http://www.cell.com/immunity/fulltext/S1074-7613(16)30288-6


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