Toll-like receptors (TLRs) initiate innate immune responses upon binding to microbial products, such as lipopolysaccharide (LPS). TLR signaling can promote inflammatory responses through pathways dependent on the adaptor protein MyD88 (myeloid differentiation factor 88) to activate production of tumor necrosis factor (TNF) and interleukin-1β (IL-1β). TLR signaling can also promote anti-inflammatory responses through pathways involving the kinase TBK1 [TRAF-associated NF-κB activator (TANK)–binding kinase 1] to activate production of type I interferon. Wang et al. found that knockdown of the E3 ubiquitin ligase Nrdp1 in macrophages increased production of proinflammatory cytokines (such as TNF and IL-1β) in response to various TLR agonists while inhibiting production of type I interferon and generated mice overexpressing full-length Nrdp1 (Nrdp1-TG mice) or a dominant-negative form of Nrdp1 (DN-Nrdp1-TG mice). Peritoneal macrophages from Nrdp1-TG mice exhibited impaired TNF production in response to various TLR agonists, whereas those from DN-Nrdp1-TG mice produced increased amounts of TNF but reduced amounts of interferon-β after TLR stimulation. Suppressing inflammatory responses during bacterial or viral infection can be beneficial, and accordingly, Nrdp1-TG mice survived lethal LPS challenges longer and exhibited reduced infection by vesicular stomatitus virus compared with DN-Nrdp1-TG or wild-type mice. In a macrophage cell line, transfected Nrdp1 directly interacted with MyD88 and TBK1 and promoted their polyubiquitination in response to LPS stimulation. Nrdp1 mediated Lys48-linked polyubiquitination of MyD88, targeting it for degradation and thereby inhibiting production of TNF. In contrast, Nrdp1 mediated Lys63-linked polyubiquitination of TBK1, stimulating its kinase activity, and overexpression of DN-Nrdp1 in a macrophage cell line prevented IFN-β production. Thus, ubiquitination of MyD88 and TBK1 by Nrdp1 favors anti-inflammatory over proinflammatory responses.
C. Wang, T. Chen, J. Zhang, M. Yang, N. Li, X. Xu, X. Cao, The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon. Nat. Immunol. 10, 744–752 (2009). [PubMed]