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Exploring regulation in the Toll‐like receptor 3 pathway
Author(s) -
Marion James D.,
Roberts Charlotte F.,
Bell Jessica K.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.952.4
Subject(s) - irf3 , microbiology and biotechnology , interferon regulatory factors , iκb kinase , kinase , tlr4 , tlr3 , toll like receptor , chemistry , signal transduction , innate immune system , biology , receptor , nf κb , biochemistry
The innate immune system is the body's first line of defense against infectious agents. Essential to this response are cellular mechanisms that recognize, sequester and eradicate these invading organisms. Toll‐like receptor 3 (TLR3), a pathogen recognition receptor, is stimulated by the viral genomic material double stranded RNA (dsRNA). TLR3 stimulation initiates a signaling cascade that leads to the production of type 1 interferon. Critical to this signaling pathway is a kinase complex, NAP1 (NAK associated protein 1)‐TBK1 (TANK Binding Kinase 1)‐IKKε (IκB kinase epsilon), which leads to the phosphorylation of IRF3 (interferon regulatory factor) and IRF7 and production of IFNβ. To control this activity, SIKE (Suppressor of IKKε) acts as a physiological inhibitor of IKKε and TBK1 activity through an undefined mechanism. Our goal is to define the inhibitory mechanism of SIKE in the kinase reaction. We have examined SIKE for post‐translation modification +/− dsRNA stimulation. We hypothesize that post‐translation modifications may mediate SIKE release from the NAP1‐TBK1‐IKKε complex allowing IRF3 and IRF7 activation. Current studies are focused on defining 1) SIKE post‐translation modifications, 2) how modification may alter SIKE protein interactions, and 3) kinetic analysis of SIKE's effect on TBK1 activity. Funding provided in part by the American Cancer Society.