The role of the protein tyrosine phosphatase PTP1B in mediating Toll-like receptors TLR7 and TLR9 function
Virology
Cell Biology
Final Report Abstract
The protein tyrosine phosphatase 1B (PTP1B) is a negative modulator of the leptin and insulin signalling pathways. Since PTP1B-/- mice are protected against the development of obesity and diabetes, this phosphatase and the inhibitors targeting its activity are the focus of intensive research. We now reveal that PTP1B has an additional and quite different role in innate immunity. We provide evidence that PTP1B is involved in the regulation of the type I interferon (IFN) response in bone marrow-derived macrophages (BMDM) and plasmacytoid dendritic cells (pDC). Upon activation of pattern recognition receptors (PRR) by synthetic PRR ligands or infection with the herpesvirus murine cytomegalovirus (MCMV), BMDM and pDC from PTP1B-deficient mice secreted lower amounts of type I IFN than cells from wild type (WT) mice. In contrast, the secretion of the proinflammatory cytokine TNFα was not affected by the absence of PTP1B. This pattern was consistent upon viral infection of mice. We found that while PTP1B deficiency does not affect the induction of IFNb1 transcription, it leads to an accumulation of type I IFN within BMDM, indicating a role for PTP1B in mediating secretion of these important antiviral cytokines. Strikingly, this effect was independent of the phosphatase activity of PTP1B, but required its proper ER membrane localisation. In summary, we have uncovered a novel function for PTP1B as a player in the PRR-mediated type I IFN response. This discovery has identified a candidate through which further investigations into its mechanism of action may provide new insights into the poorly understood mechanisms of type I IFN secretion. Understanding in molecular detail how type I IFN is secreted would greatly contribute to the field of infection biology and autoimmunity and may open up new avenues for therapies of autoimmune disorders.
Publications
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(2017). The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. PLoS Pathog. 13(5):e1006382
Chan B, Gonçalves Magalhães V, Lemmermann NAW, Juranić Lisnić V, Stempel M, Bussey KA, Reimer E, Podlech J, Lienenklaus S, Reddehase MJ, Jonjić S, Brinkmann MM
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(2018). Endosomal Toll-Like Receptors 7 and 9 Cooperate in Detection of Murine Gammaherpesvirus 68 Infection. J Virol. 93(3)
Bussey KA, Murthy S, Reimer E, Chan B, Hatesuer B, Schughart K, Glaunsinger B, Adler H, Brinkmann MM
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(2018). The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport. Immunity. 48(5):911-922.e7
Pelka K, Bertheloot D, Reimer E, Phulphagar K, Schmidt SV, Christ A, Stahl R, Watson N, Miyake K, Hacohen N, Haas A, Brinkmann MM, Marshak-Rothstein A, Meissner F, Latz E
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(2019). Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway. Med Microbiol Immunol
Stempel M, Chan B, Brinkmann MM
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(2019). The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-κB signaling and STING's dual role during MCMV infection. The EMBO Journal. 38(5)
Stempel M, Chan B, Juranić Lisnić V, Krmpotić A, Hartung J, Paludan SR, Füllbrunn N, Lemmermann NA, Brinkmann MM
