Association Of β-arrestom And TRAF6 Negatively Regulates Toll-like Receptor-interleukin 1 Receptor Signaling

The activation of immune responses through Toll-like receptor (TLR) ?interleukin 1receptor (IL-1R) signalling is critical for host defence. Excessive or inappropriateactivation as a result of unrestrained TLR?IL-1R signals can, however, bedetrimental to the host. Therefore TLR?IL-1R signals must be under preciseregulation. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is criticalfor mediating TLR?IL-1R signalling and subsequent activation of NF-κB and AP-1,transcriptional activators of innate immunity. β-Arrestins are multifunctionalmolecules that, in addition to their well-established roles in desensitisation andendocytosis of different kinds of cell surface receptors, bind various signallingmolecules to modulate their phosphorylation, ubiquitination, and/or subcellulardistribution. Here we show that β-arrestins directly interacts with TRAF6 afterTLR?IL-1R activation. Formation of the β-arrestin-TRAF6 complex preventsauto-ubiquitination of TRAF6 and activation of NF-κB and AP-1.β-Arrestin-deficient MEFs showed increased IKK activity and MAPK activationafter LPS stimulation. β-Arrestin2-deficient macrophages produced higherconcentrations of proinflammatory cytokines in response to a variety of pathogenicstimuli. Notably, endotoxin treated β-arrestin 2-deficient mice expressed higheramounts of proinflammatory cytokines and were more susceptible to endotoxicshock. Thus β-arrestins are essential negative regulators of innate immune activationvia TLR?IL-1R signalling.