Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM

Huai, Wanwan; Song, Hui; Wang, Limin; Li, Bingqing; Zhao, Jing; Han, Lihui; Gao, Chengjiang; Jiang, Guosheng; Zhang, Lining; Zhao, Wei

doi:10.4049/jimmunol.1402183

Cited by 41 publications

(34 citation statements)

References 33 publications

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“…Three days later, peritoneal exudate cells were harvested and incubated. Two hours later, nonadherent cells were removed and the adherent monolayer cells were used as peritoneal macrophages (19)(20)(21). THP-1, HeLa, and human embryonic kidney (HEK) 293T cells were obtained from American Type Culture Collection (Manassas, VA).…”

Section: Mice and Cell Culturementioning

confidence: 99%

“…Luciferase activities were measured with a Dual-Luciferase reporter assay system (Promega) according to the manufacturer's instructions (19)(20)(21). Data are normalized for transfection efficiency by subtracting firefly luciferase activity with that of Renilla luciferase.…”

Section: Luciferase Assaymentioning

confidence: 99%

“…18066) (22). Expression plasmids for RIG-I, MDA5, MAVS, TRIF, TBK1, and IRF3 5D were described before (19,21). …”

Section: Mice and Cell Culturementioning

confidence: 99%

“…Nuclear proteins were extracted by NE-PER protein extraction reagent (Pierce) according to the manufacturer's instructions. Equal amounts of extracts were separated by SDS-PAGE and then were transferred onto nitrocellulose membranes for immunoblot analysis (19)(20)(21).…”

Section: Western Blotmentioning

confidence: 99%

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MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

Song

Huai

et al. 2016

The Journal of Immunology

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Neddylation is a posttranslational protein modification that conjugates ubiquitin-like protein neural precursor cell–expressed developmentally downregulated protein 8 (NEDD8) to target proteins and regulates diverse cellular processes. MLN4924, a novel NEDD8 activating enzyme inhibitor, which has emerged as a promising anticancer drug, has a multifaceted function by inhibiting the process of neddylation. However, the potential roles of MLN4924 and neddylation in IFN-β production remain unknown. In this study, we show that MLN4924 inhibits TLR3/4- and retinoic acid–inducible gene-I–induced IFN-β expression in different cells, whereas NEDD8 knockdown had no effects on IFN-β expression. The ability of the MLN4924 to inhibit IFN-β production was confirmed in vivo, as mice treated with MLN4924 exhibited decreased levels of IFN-β upon LPS or polyinosinic-polycytidylic acid stimulation. Furthermore, we show that MLN4924 inhibits IFN regulatory factor 3 (IRF3) transcriptional activation and prevents IRF3 binding to IFN-β promoter. Our findings suggest that MLN4924 inhibits TLR3/4- and retinoic acid–inducible gene-I–induced IFN-β expression by preventing IRF3 binding to the IFN-β promoter, with a neddylation-independent manner. Therefore, our results provide new insight into the mechanism of MLN4924 and may have significant implications for the treatment of MLN4924.

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Section: Mice and Cell Culturementioning

confidence: 99%

Section: Luciferase Assaymentioning

confidence: 99%

“…18066) (22). Expression plasmids for RIG-I, MDA5, MAVS, TRIF, TBK1, and IRF3 5D were described before (19,21). …”

Section: Mice and Cell Culturementioning

confidence: 99%

Section: Western Blotmentioning

confidence: 99%

See 2 more Smart Citations

MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

Song

Huai

et al. 2016

The Journal of Immunology

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“…Indeed, we showed that rabies virus (RABV) peptides encoding a PBM can target the PDZ domain of PTPN4 (PTPN4-PDZ) and antagonize the function of PTPN4, leading to cell death (6). We optimized such pro-apoptotic peptides and designed the Cyto8-RETEV sequence, that is so far the most affine ligand of PTPN4-PDZ and the best inducer of cell death (15).Four endogenous partners of PTPN4 have been reported: the glutamate receptor ␦2 and ⑀ subunits, the T-cell receptor subunit, the CrkI oncoprotein, and the TRIF (TIR domain-containing adaptor-inducing interferon-B)-related adaptor molecule TRAM (3,5,16,17). Nevertheless, the natural ligands of PTPN4 involved in the regulation of cell homeostasis remain unknown.…”

mentioning

confidence: 99%

Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

Maisonneuve

Caillet‐Saguy

Vaney

et al. 2016

Journal of Biological Chemistry

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The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cell death induction in neuroblastoma and glioblastoma cell lines in a PDZ⅐PDZ binding motifs-dependent manner, but the cellular partners of PTPN4 involved in cell protection are unknown. Here, we described the mitogen-activated protein kinase p38␥ as a cellular partner of PTPN4. The main contribution to the p38␥⅐PTPN4 complex formation is the tight interaction between the C terminus of p38␥ and the PDZ domain of PTPN4. We solved the crystal structure of the PDZ domain of PTPN4 bound to the p38␥ C terminus. We identified the molecular basis of recognition of the C-terminal sequence of p38␥ that displays the highest affinity among all endogenous partners of PTPN4. We showed that the p38␥ C terminus is also an efficient inducer of cell death after its intracellular delivery. In addition to recruiting the kinase, the binding of the C-terminal sequence of p38␥ to PTPN4 abolishes the catalytic autoinhibition of PTPN4 and thus activates the phosphatase, which can efficiently dephosphorylate the activation loop of p38␥. We presume that the p38␥⅐PTPN4 interaction promotes cellular signaling, preventing cell death induction. PTPN45 is a non-receptor-tyrosine phosphatase (PTP) with functions in T cell signaling, learning, spatial memory, and cerebellar synaptic plasticity (1-3). Its overexpression reduces cell proliferation in COS-7 cells and suppresses CrkI-mediated cell growth and mobility in HEK293T cells (4, 5). PTPN4 also regulates neuronal cell homeostasis by protecting neurons against apoptosis (5, 6). PTPN4 is a large modular protein containing three domains, an N-terminal FERM domain, a PDZ domain, and a C-terminal catalytic tyrosine phosphatase domain (7). PDZ domains are protein-protein interaction domains, which play a central role in cell signaling by favoring spatial contacts between enzymes and their substrates or, more generally, by assembling and/or regulating protein networks (8, 9). Thus, disrupting the interactions between PDZ domains and PDZ binding motifs (PBM) can trigger profound alterations in cell signaling pathways (10 -12). Such disruptions of PDZ⅐PBM complexes are used by viruses to hijack cell signaling pathways to their own advantage and can also be obtained by treating cells with an excess of cell penetrating peptide encoding a PBM (13). Indeed, we showed that rabies virus (RABV) peptides encoding a PBM can target the PDZ domain of PTPN4 (PTPN4-PDZ) and antagonize the function of PTPN4, leading to cell death (6). We optimized such pro-apoptotic peptides and designed the Cyto8-RETEV sequence, that is so far the most affine ligand of PTPN4-PDZ and the best inducer of cell death (15).Four endogenous partners of PTPN4 have been reported: the glutamate receptor ␦2 and ⑀ subunits, the T-cell receptor subunit, the CrkI oncoprotein, and the TRIF (TIR domain-containing adaptor-inducing interferon-B)-related adaptor molecule TRAM (3,5,16,17). Nevertheless, the natural ligands of PTPN4 involved in the regulation of cell homeos...

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TLR4 phosphorylation at tyrosine 672 activates the ERK/c‐FOS signaling module for LPS‐induced cytokine responses in macrophages

et al. 2023

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TLRs engage numerous adaptor proteins and signaling molecules, enabling a complex series of post-translational modifications (PTMs) to mount inflammatory responses. TLRs themselves are post-translationally modified following ligand-induced activation, with this being required to relay the full spectrum of proinflammatory signaling responses. Here, we reveal indispensable roles for TLR4 Y672 and Y749 phosphorylation in mounting optimal LPS-inducible inflammatory responses in primary mouse macrophages. LPS promotes phosphorylation at both tyrosine residues, with Y749 phosphorylation being required for maintenance of total TLR4 protein levels and Y672 phosphorylation exerting its pro-inflammatory effects more selectively by initiating ERK1/2 and c-FOS phosphorylation. Our data also support a role for the TLR4-interacting membrane proteins SCIMP and the SYK kinase axis in mediating TLR4 Y672 phosphorylation to permit downstream inflammatory responses in murine macrophages. The corresponding residue in human TLR4 (Y674) is also required for optimal LPS signaling responses. Our study, thus, reveals how a single PTM on one of the most widely studied innate immune receptors orchestrates downstream inflammatory responses.

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Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM

Cited by 41 publications

References 33 publications

MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production

Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

TLR4 phosphorylation at tyrosine 672 activates the ERK/c‐FOS signaling module for LPS‐induced cytokine responses in macrophages

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