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

Exp Cell Res. 2019 Oct 1;383(1):111497. doi: 10.1016/j.yexcr.2019.111497. Epub 2019 Jul 10.

Abstract

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.

Keywords: K63-linked ubiquitination; LRRC62; NF-κB; TAK1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Deubiquitinating Enzyme CYLD / genetics
  • Deubiquitinating Enzyme CYLD / metabolism*
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein Binding
  • Proteolysis
  • Signal Transduction
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism*
  • Ubiquitination*

Substances

  • Membrane Proteins
  • NF-kappa B
  • Toll-Like Receptors
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD