Abstract
Toll-like receptors (TLRs) have critical roles in innate immunity and inflammation and the detailed mechanisms by which TLR signaling is fine tuned remain unclear. Keratin 8 (CK8) belongs to the type II keratin family and is the major compontent of the intermediate filaments of simple or single-layered epithelia. Here we report that down-regulation of CK8 in mice enhanced TLR-mediated responses, rendering mice more susceptible to lipopolysaccharide (LPS)-induced endotoxin shock and Escherichia coli–caused septic peritonitis with reduced survival, elevated levels of inflammation cytokines and more severe tissue damage. We found that CK8 suppressed TLR-induced nuclear factor (NF)-κB activation and interacted with the adaptor tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) to prevent its polyubiquitination. Our findings demonstrate a novel role of CK8 in negative regulation of TLR/NF-κB signaling and highlight a previously unidentified nonclassical function for CK8 in limiting inflammatory responses.
Highlights
Expressed in epithelia cells, has over 20 members (Keratin 1–20) that form obligate noncovalent heteropolymers of at least one type I (Keratin 9–20) and one type II keratin (Keratin 1–8)[16]
We show that CK8 functions as a negative regulator of Toll-like receptor (TLR)/NF-κB signaling by inhibiting TRAF6 polyubiquitination
We found that CK8+/− mice produced more TNFαat 1 h and IL-6 at 24 h, and lower levels of IL-10 at 1 h than CK8+/+ mice (P < 0.05, Fig. 1C)
Summary
Expressed in epithelia cells, has over 20 members (Keratin 1–20) that form obligate noncovalent heteropolymers of at least one type I (Keratin 9–20) and one type II keratin (Keratin 1–8)[16]. CK8 binds to the cytoplasmic domain of TNF receptor type 2 (TNFR2) and moderates the TNF-dependent activation of NF-κB transcription factor. It is as yet unknown whether CK8 plays a role in TLR/NF-κB signaling. We show that CK8 functions as a negative regulator of TLR/NF-κB signaling by inhibiting TRAF6 polyubiquitination. CK8+/− mice showed higher sensitivity to LPS-induced endotoxin shock and E.coli-caused septic peritonitis with increased mortality, suggesting a crucial role of CK8 in TLR-induced inflammatory response. Our study has identified a previously unrecognized role for CK8 in controlling NF-κBsignaling by inhibiting polyubiquitination of TRAF6, negatively regulating the TLR-mediated inflammatory response
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