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

The role of Pellino proteins in Toll-like receptor (TLR) signaling is not completely understood. Sun and colleagues now find that Pellino1 ubiquitinates the signaling molecule RIP1 and is essential for TRIF-dependent TLR signal transduction in mice. Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered 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 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.