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ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in
Saki Takayanagi1, Kengo Watanabe2, Takeshi Maruyama1
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Scientific Reports
|November 11, 2021
Summary
Apoptosis signal-regulating kinase 1 (ASK1) suppresses innate immunity in brown fat, aiding brown adipocyte maintenance. ASK1 inhibits the NOD-RIPK2 pathway, reducing inflammatory cytokines and supporting thermogenesis.
Area of Science:
- Immunology
- Cell Biology
- Metabolism
Background:
- Adipose tissue functions as an immunological organ, with white adipose tissue inflammation extensively studied.
- Regulatory mechanisms of inflammation in brown adipose tissues are less understood.
- Apoptosis signal-regulating kinase 1 (ASK1) was previously identified as crucial for brown adipocyte maturation via the PKA-ASK1-p38 pathway, promoting UCP1 induction.
Purpose of the Study:
- To investigate the role of ASK1 in regulating inflammation and maintaining brown adipocytes.
- To identify novel interactors of ASK1 in brown adipose tissue.
- To elucidate the molecular mechanisms by which ASK1 influences brown adipocyte function.
Main Methods:
- Utilized a novel chemical pull-down method with analog sensitive kinase allele (ASKA) technology to identify endogenous ASK1 interactors.
- Investigated the interaction between ASK1 and receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in brown adipocytes.
- Examined the effect of ASK1 on the NOD-RIPK2 signaling pathway and inflammatory cytokine production.
- Employed an in vitro model for intercellular regulation to assess ASK1's impact on UCP1 expression.
Main Results:
- Identified receptor-interacting serine/threonine-protein kinase 2 (RIPK2) as a novel ASK1 interactor in brown adipocytes.
- Demonstrated that ASK1 disrupts the RIPK2 signaling complex, inhibiting the NOD-RIPK2 pathway.
- Showed that ASK1 suppresses the production of inflammatory cytokines.
- Indicated that ASK1 promotes UCP1 expression by suppressing inflammatory cytokine production, suggesting a role in intercellular regulation.
Conclusions:
- ASK1 plays a critical role in suppressing innate immune pathways within brown adipose tissue, contributing to brown adipocyte maintenance.
- ASK1 inhibits the NOD-RIPK2 pathway, thereby reducing inflammatory cytokine production and potentially enhancing thermogenesis.
- ASK1 may have an auxiliary role in brown adipocyte maintenance by counteracting the thermogenesis-suppressive effects of the NOD-RIPK2 pathway.
