The p38-interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1.
TAK1 activity sensor
USP4 scaffold
immunoreceptor signaling
negative regulator
p38IP
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
03 07 2020
03 07 2020
Historique:
received:
04
03
2019
revised:
02
04
2020
accepted:
16
04
2020
pubmed:
16
5
2020
medline:
28
4
2021
entrez:
16
5
2020
Statut:
ppublish
Résumé
Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T-cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the polyUb chain transfer and the higher binding affinity of TAK1 and p38IP for polyUb-bound TAB2 and TAK1, respectively. Moreover, p38IP scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.
Identifiants
pubmed: 32410369
doi: 10.15252/embr.201948035
pmc: PMC7332986
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Lipopolysaccharides
0
NF-kappa B
0
Receptors, Antigen, T-Cell
0
USP4 protein, human
0
Ubiquitin-Specific Proteases
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e48035Subventions
Organisme : National Natural Science Foundation of China (NSFC)
ID : 31670893
Pays : International
Organisme : National Natural Science Foundation of China (NSFC)
ID : 31370886
Pays : International
Organisme : National Natural Science Foundation of China (NSFC)
ID : 30571699
Pays : International
Organisme : The Ministry of Science and Technology of China
ID : 2013CB835300
Pays : International
Organisme : The open research found of SKLCSB in Xiamen University
ID : SKLCSB2019KF017
Pays : International
Informations de copyright
© 2020 The Authors.
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