LRRC62 attenuates Toll-like receptor signaling by deubiquitinating TAK1 via CYLD.

TGF-β-activated kinase 1 (TAK1) plays a pivotal role in Toll-like receptor (TLR) signaling pathway. However, the mechanisms controlling its activity remain poorly understood. Here, we show that leucine-rich repeat containing 62 (LRRC62), a previously uncharacterized protein, negatively regulates TLR signaling by targeting TAK1. Expression of LRRC62 inhibits the TLRs-induced production of pro-inflammatory cytokine, whereas deficiency in LRRC62 enhances the activation of NF-κB and MAPK signaling and increases the production of pro-inflammatory cytokines. Mechanically, LRRC62 functions as an adaptor to recruit deubiquitinase CYLD to TAK1, thus inhibits the K63-linked poly-ubiquitination and activation of TAK1. Together, our findings uncover an unrecognized mechanism by which LRRC62 antagonizes the activation of TAK1 in a CYLD-mediated deubiquitination-dependent manner, thereby balancing Toll-like receptor signaling to avert overzealous inflammation.