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

Jindong Zhang1, Jiayu Ou2, Xiaoye Wan3

  • 1Immunotherapy Institute, Fujian Medical University, Fuzhou, 350004, PR China; School of Basic Medical Science, Fujian Medical University, Fuzhou, 350004, PR China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, PR China.

Experimental Cell Research
|July 14, 2019
PubMed

Insights

Leucine-rich repeat containing 62 (LRRC62) negatively regulates Toll-like receptor (TLR) signaling by inhibiting TGF-β-activated kinase 1 (TAK1) activation. This mechanism involves recruiting deubiquitinase CYLD to TAK1, averting excessive inflammation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Toll-like receptor (TLR) signaling is crucial for innate immunity.
  • The activation mechanisms of TGF-β-activated kinase 1 (TAK1), a key regulator in TLR pathways, are not fully understood.
  • Understanding TLR signaling regulation is vital for controlling inflammatory responses.

Purpose of the Study:

  • To identify novel regulators of TLR signaling.
  • To elucidate the mechanism by which leucine-rich repeat containing 62 (LRRC62) modulates TAK1 activity.
  • To investigate the role of LRRC62 in inflammatory cytokine production.

Main Methods:

  • Investigated the role of LRRC62 in TLR signaling pathways.
  • Assessed the impact of LRRC62 expression on pro-inflammatory cytokine production.
  • Utilized molecular assays to determine the interaction between LRRC62, TAK1, and CYLD.
  • Examined the effect of LRRC62 on NF-κB and MAPK signaling activation.

Main Results:

  • LRRC62 negatively regulates TLR-induced pro-inflammatory cytokine production.
  • LRRC62 deficiency enhances NF-κB and MAPK signaling activation.
  • LRRC62 acts as an adaptor protein to recruit CYLD to TAK1.
  • LRRC62 inhibits TAK1 activation by promoting CYLD-mediated deubiquitination.

Conclusions:

  • LRRC62 is a novel negative regulator of TLR signaling.
  • LRRC62 antagonizes TAK1 activation through CYLD-dependent deubiquitination.
  • This pathway balances TLR signaling to prevent excessive inflammation.
Keywords:
K63-linked ubiquitinationLRRC62NF-κBTAK1

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