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TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages

Kyung-Hye Roh1, Yeojin Lee1, Je-Hyun Yoon2

  • 1Department of Life Sciences, Korea University, Seoul, 02841, Korea.

Cellular and Molecular Life Sciences : CMLS
|September 25, 2020
PubMed

Insights

Mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) negatively regulates Toll-like receptor 4 (TLR4) signaling. Ablating MST1/STK4 increases susceptibility to septic shock by enhancing inflammatory responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Pattern-recognition receptors, like Toll-like receptors (TLRs), are crucial for initiating immune responses against pathogens.
  • The Toll-like receptor 4 (TLR4) pathway, activated by lipopolysaccharide (LPS), plays a key role in inflammation and sepsis.

Purpose of the Study:

  • To investigate the role of mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) in regulating the TLR4-NF-κB signaling pathway.
  • To determine the impact of MST1/STK4 on LPS-induced inflammatory responses and septic shock.

Main Methods:

  • Utilized myeloid-specific genetic ablation of MST1/STK4 in mice.
  • Analyzed NF-κB activation and proinflammatory cytokine production in bone marrow-derived macrophages (BMDMs) stimulated with LPS.
  • Investigated the interaction between MST1/STK4 and TRAF6, including ubiquitination events.

Main Results:

  • Genetic ablation of MST1/STK4 in myeloid cells heightened susceptibility to LPS-induced septic shock.
  • Loss of MST1/STK4 enhanced LPS-induced NF-κB activation and proinflammatory cytokine production in BMDMs.
  • MST1/STK4 was found to inhibit TRAF6 autoubiquitination and downstream signaling, while TRAF6-mediated ubiquitination of MST1/STK4 initiated negative feedback.

Conclusions:

  • MST1/STK4 acts as a negative regulator of the LPS-induced TLR4-NF-κB signaling pathway.
  • MST1/STK4 plays a critical role in controlling macrophage activation and inflammatory responses.
  • Targeting MST1/STK4 may offer therapeutic strategies for inflammatory diseases and sepsis.
Keywords:
LipopolysaccharidesMST1/STK4NF-κBTRAF6

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