A Toll-like receptor-responsive kinase, protein kinase R, is inactivated in endotoxin tolerance through differential K63/K48 ubiquitination.
Overwhelming inflammation triggered by systemic infection in bacterial sepsis contributes to the pathology of this condition. Toll-like receptors (TLRs) are important in early septic inflammation. As a safeguard, the innate immune system has evolved to counter excessive inflammation through the induction of "tolerance." In endotoxin tolerance, TLR signaling is inhibited and/or attenuated by multiple mechanisms that mitigate the ability of lipopolysaccharide (LPS) to activate critical kinases through TLR4. Here, we describe a novel mechanism. Protein kinase R (PKR), a kinase normally activated by a subset of TLRs, is rendered unresponsive to LPS in endotoxin-tolerized cells. In its naive state, PKR is subject to K63-linked ubiquitination (Ub), followed by K48-linked Ub, in response to LPS. In tolerance, the kinetics of this differential Ub is altered, resulting in a predominance of K48-linked chains, concomitant with a loss of PKR activation. These findings provide a novel mechanism by which a TLR-responsive kinase may be rendered inactive in tolerance.
Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA.
Darren J
DJ
Perkins
Nilofer
N
Qureshi
Stefanie N
SN
Vogel
D000818:Animals; D002478:Cells, Cultured; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D007108:Immune Tolerance; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D054875:Ubiquitination; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D004731:Endotoxins; D051197:Toll-Like Receptor 4; D019892:eIF-2 Kinase