COP9 plays a role in plant innate immunity. The role of COP9 in mammalian innate 
immune responses is unknown. Here, we show that the COP9 signalosome subunit 5 
(CSN5) is required for activation of proinflammatory kinases p38 and Erk and for 
down-regulation of the expression of genes regulated by nuclear factor 
E2-related factor 2. Mice with myeloid-specific CSN5 deficiency have lower 
mortality in polymicrobial sepsis. CSN5 is required for both Toll-like receptor 
(TLR) and reactive oxygen species-mediated deneddylation of Cul3, which is 
essential for Cul3/Keap1-mediated degradation of nuclear factor E2-related 
factor 2. On the basis of our results COP9 subunit CSN5 is considered to be an 
essential component of mammalian innate immunity.