PMID- 32975614
OWN - NLM
STAT- MEDLINE
DCOM- 20210329
LR  - 20240226
IS  - 1420-9071 (Electronic)
IS  - 1420-682X (Linking)
VI  - 78
IP  - 5
DP  - 2021 Mar
TI  - TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-kappaB signaling 
      pathway in macrophages.
PG  - 2315-2328
LID - 10.1007/s00018-020-03650-4 [doi]
AB  - Pattern-recognition receptors including Toll-like receptors (TLRs) recognize 
      invading pathogens and trigger an immune response in mammals. Here we show that 
      mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as 
      a negative regulator of lipopolysaccharide (LPS)-induced activation of the 
      TLR4-NF-kappaB signaling pathway associated with inflammation. Myeloid-specific 
      genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced 
      septic shock. Ablation of MST1/STK4 also enhanced NF-kappaB activation triggered by 
      LPS in bone marrow-derived macrophages (BMDMs), leading to increased production 
      of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited 
      TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced 
      by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of 
      MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback 
      regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production 
      in macrophages. Together, our findings suggest that MST1/STK4 functions as a 
      negative modulator of the LPS-induced NF-kappaB signaling pathway during macrophage 
      activation.
FAU - Roh, Kyung-Hye
AU  - Roh KH
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Lee, Yeojin
AU  - Lee Y
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Yoon, Je-Hyun
AU  - Yoon JH
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, 29425, USA.
FAU - Lee, Danbi
AU  - Lee D
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Kim, Eunju
AU  - Kim E
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Park, Eunchong
AU  - Park E
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Lee, In Young
AU  - Lee IY
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Kim, Tae Sung
AU  - Kim TS
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Song, Hyun Kyu
AU  - Song HK
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea.
FAU - Shin, Jaekyoon
AU  - Shin J
AD  - Department of Molecular Cell Biology, Samsung Biomedical Research Institute, 
      Sungkyunkwan University School of Medicine, Suwon, 16419, Korea.
FAU - Lim, Dae-Sik
AU  - Lim DS
AD  - Department of Biological Sciences, National Creative Research Initiatives Center, 
      Biomedical Research Center, Graduate School of Medical Science and Engineering, 
      Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea.
FAU - Choi, Eui-Ju
AU  - Choi EJ
AUID- ORCID: 0000-0002-3642-0432
AD  - Department of Life Sciences, Korea University, Seoul, 02841, Korea. 
      ejchoi@korea.ac.kr.
LA  - eng
GR  - 2016H1A2A1907478/Ministry of Science and ICT of Korea/
GR  - NRF-2020R1A2C2011392/Ministry of Science and ICT of Korea/
PT  - Journal Article
DEP - 20200925
PL  - Switzerland
TA  - Cell Mol Life Sci
JT  - Cellular and molecular life sciences : CMLS
JID - 9705402
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Sequestosome-1 Protein)
RN  - 0 (Sqstm1 protein, mouse)
RN  - 0 (TNF Receptor-Associated Factor 6)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - EC 2.7.1.- (Stk4 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cytokines/blood/genetics/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophage Activation/drug effects
MH  - Macrophages/cytology/drug effects/*metabolism
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - NF-kappa B/*metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Sepsis/blood/genetics/metabolism
MH  - Sequestosome-1 Protein/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Survival Analysis
MH  - TNF Receptor-Associated Factor 6/genetics/*metabolism
MH  - Toll-Like Receptor 4/genetics/*metabolism
MH  - Ubiquitination/drug effects
MH  - Mice
OTO - NOTNLM
OT  - Lipopolysaccharides
OT  - MST1/STK4
OT  - NF-kappaB
OT  - TRAF6
EDAT- 2020/09/26 06:00
MHDA- 2021/03/30 06:00
CRDT- 2020/09/25 12:15
PHST- 2020/05/19 00:00 [received]
PHST- 2020/09/15 00:00 [accepted]
PHST- 2020/08/24 00:00 [revised]
PHST- 2020/09/26 06:00 [pubmed]
PHST- 2021/03/30 06:00 [medline]
PHST- 2020/09/25 12:15 [entrez]
AID - 10.1007/s00018-020-03650-4 [pii]
AID - 10.1007/s00018-020-03650-4 [doi]
PST - ppublish
SO  - Cell Mol Life Sci. 2021 Mar;78(5):2315-2328. doi: 10.1007/s00018-020-03650-4. 
      Epub 2020 Sep 25.