The p38‐interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1
- 15 May 2020
- journal article
- research article
- Published by EMBO in EMBO Reports
- Vol. 21 (7), e48035
- https://doi.org/10.15252/embr.201948035
Abstract
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.Keywords
Funding Information
- National Natural Science Foundation of China (31370886, 31670893, 30571699)
This publication has 71 references indexed in Scilit:
- NF-κB signaling in inflammationSignal Transduction and Targeted Therapy, 2017
- A novel miR-200b-3p/p38IP pair regulates monocyte/macrophage differentiationCell Discovery, 2016
- The p38-interacting Protein (p38IP) Regulates G2/M Progression by Promoting α-Tubulin Acetylation via Inhibiting Ubiquitination-induced Degradation of the Acetyltransferase GCN5Online Journal of Public Health Informatics, 2013
- Coordinated regulation of autophagy by p38α MAPK through mAtg9 and p38IPThe EMBO Journal, 2009
- The Human SPT20-Containing SAGA Complex Plays a Direct Role in the Regulation of Endoplasmic Reticulum Stress-Induced GenesMolecular and Cellular Biology, 2009
- Human ATAC Is a GCN5/PCAF-containing Acetylase Complex with a Novel NC2-like Histone Fold Module That Interacts with the TATA-binding ProteinOnline Journal of Public Health Informatics, 2008
- p38 and a p38-Interacting Protein Are Critical for Downregulation of E-Cadherin during Mouse GastrulationCell, 2006
- TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivoGenes & Development, 2005
- Essential function for the kinase TAK1 in innate and adaptive immune responsesNature Immunology, 2005
- Activation and signaling of the p38 MAP kinase pathwayCell Research, 2005