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The p38-interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1

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-?B 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-?B 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.

SUBMITTER: Prof. Yingqiu Li

PROVIDER: S-SCDT-EMBOR-2019-48035V1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BACKGROUND: Abnormal activation of the NF-?B pathway is closely related to tumorigenesis and chemoresistance. Therefore, microRNAs that possess the NF-?B inhibitory activity may provide novel targets for anti-cancer therapy. miR-26 family members have been shown to be frequently downregulated in hepatocellular carcinoma (HCC) and correlated with the poor survival of HCC patients. To date, there is no report disclosing the regulatory role of miR-26 on the NF-?B pathway and its biological significance. METHODS: The effects of miR-26b on the NF-?B signaling pathway and the chemosensitivity of cancer cells were examined in two HCC cell lines, QGY-7703 and MHCC-97H, using both gain- and loss-of-function studies. The correlation between miR-26b level and apoptosis rate was further investigated in clinical HCC specimens. RESULTS: Both TNF? and doxorubicin treatment activated the NF-?B signaling pathway in HCC cells. However, the restoration of miR-26b expression significantly inhibited the phosphorylation of I?B? and p65, blocked the nuclear translocation of NF-?B, reduced the NF-?B reporter activity, and consequently abrogated the expression of NF-?B target genes in TNF? or doxorubicin-treated HCC cells. Furthermore, the ectopic expression of miR-26b dramatically sensitized HCC cells to the doxorubicin-induced apoptosis, whereas the antagonism of miR-26b attenuated cell apoptosis. Consistently, the miR-26b level was positively correlated with the apoptosis rate in HCC tissues. Subsequent investigations revealed that miR-26b inhibited the expression of TAK1 and TAB3, two positive regulators of NF-?B pathway, by binding to their 3'-untranslated region. Moreover, knockdown of TAK1 or TAB3 phenocopied the effects of miR-26b overexpression. CONCLUSIONS: These data suggest that miR-26b suppresses NF-?B signaling and thereby sensitized HCC cells to the doxorubicin-induced apoptosis by inhibiting the expression of TAK1 and TAB3. Our findings highlight miR-26b as a potent inhibitor of the NF-?B pathway and an attractive target for cancer treatment.

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The p38-interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1

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