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Researchers from School of Life Sciences of Sun Yat-sen University have identified a novel suppressor of immunoreceptor signaling

Last updated :2020-06-11

Source: School of Life Sciences
Written by: School of Life Sciences
Edited by: Tan Rongyu, Wang Dongmei

Both adaptive and innate immunoreceptor signaling are tightly regulated at multiple levels by a series of negative regulators. Loss of negative regulators can cause hyperactivation of immune cells and lead to autoimmune and inflammatory diseases. Identifying novel negative regulators of immunoreceptor signaling will provide attractive targets for therapeutic intervention in autoimmune and inflammatory diseases and cancer because inhibitors of negative regulators might enhance antitumor immunity.

Recently, Prof. Yingqiu Li’s research group from School of Life Sciences of Sun Yat-sen University (SYSU) has identified p38IP molecule as a novel suppressor of immunoreceptor signaling and revealed the underlying mechanism. The study has been published in EMBO Reports, entitled “The p38-interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1”.

 
 p38IP suppresses immunoreceptor signaling via a dual mechanism

In this study, the researchers show that p38IP suppresses T-cell receptor (TCR)/LPS-activated NF-κB and p38 MAPK 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. They further revealed p38IP is an intrinsic suppressor of TAK1 through a dual mechanism: disassembling the TAK1-TAB complex by competitively binding to TAK1 and specifically delivering USP4 to activated TAK1 to deubiquitinate it. Interestingly, p38IP dynamically interacts with TAK1 upon stimulation, because of the polyUb chain transfer and the changes in affinity upon polyUb-binding. These findings establish that p38IP is a negative regulator of TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.

Dr. Xu-Dong Wang and Ph.D. student Chen-Si Zhao from School of Life Sciences of SYSU are co-first authors. This research was supported by the National Natural Science Foundation of China.

Link to the paper: https://www.embopress.org/doi/10.15252/embr.201948035