Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production

Toll-like receptors (TLRs) play a pivotal role in innate immunity and inflammation. Here we showed that genetic deficiency of Peli1, an E3 ubiquitin ligase, attenuates induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and renders mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IκB kinase (IKK) and its downstream target transcription factor NF-κB, but was dispensable for IKK–NF-κB activation induced by several other TLRs and the interleukin-1 receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. These findings suggest that Peli1 is a ubiquitin ligase needed for transmission of TRIF-dependent TLR signals.