The role of the protein tyrosine phosphatase PTP1B in mediating Toll-like receptors TLR7 and TLR9 function

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Toll-like receptors (TLRs) exemplify a key cell biological concept: Subcellular localisation determines the outcome of biological processes. It has been widely demonstrated that TLR function needs to be precisely regulated to prevent adverse effects upon recognition of self ligands, which can lead to autoimmune or inflammatory disorders. In recent years, the trafficking and localisation of TLRs has emerged as a primary discriminatory mechanism between self versus non-self, as well as the induction of distinct signalling cascades. Currently, the precise regulation of endosomally located nucleic acid-sensing TLRs and their crucial cofactor UNC93B is still incompletely understood.We have accumulated several lines of evidence that the protein tyrosine phosphatase PTP1B is a novel player in the innate immune response elicited by endosomally located TLRs 7 and 9. PTP1B was identified in a proteomics approach as a novel interacting partner of UNC93B. We can show that the type I interferon response in plasmacytoid dendritic cells upon TLR7/9 stimulation and murine cytomegalovirus (MCMV) infection is impaired in the absence of PTP1B in vitro. In contrast, the proinflammatory cytokine response is intact in PTP1B deficient cells and mice upon TLR7/9 stimulation. Collectively, our data suggest a potential role for PTP1B as a critical positive regulator of the TLR7- and TLR9-dependent type I IFN response. In the proposed project we will define the role of PTP1B in TLR7 and TLR9 function in primary innate immune cells with the following aims: (1) Using cell biological and immunological methods we will elucidate whether PTP1B regulates either trafficking of TLR7/9 to specific subcellular compartments or the downstream type I IFN signalling pathway induced by TLR7/9 upon ligand binding.(2) We will decipher whether the phosphatase activity of PTP1B is crucial for its positive regulatory role on TLR signalling and aim to identify the substrate(s) or further binding partners of PTP1B.(3) In vitro, PTP1B is important for the type I IFN response to MCMV infection. We will analyse the role of PTP1B in the innate immune response to infection with MCMV and the Gram-positive bacterium Staphylococcus aureus in vivo.With these studies we expect to gain mechanistic insights into the regulation of nucleic acid-sensing TLRs and obtain knowledge about the specialised compartments associated with TLR signalling. Elucidating the molecular pathways that regulate TLR function will ultimately broaden therapeutic opportunities to treat autoimmune disease.