ArticlePLoS neglected tropical diseases2008
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif.
Article in PLoS neglected tropical diseases, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 98 citations in OpenAlex.
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- Evidence of a conserved mammalian immunosuppression mechanism inFrontiers in immunology · 2023Article
- Regulation of innate immune signaling by IRAK proteins.Frontiers in immunology · 2023Review
- The pathogenicity and virulence of Leishmania - interplay of virulence factors with host defenses.Virulence · 2022Review
- Characterization ofParasitology · 2022Article
- Phosphatases in toll-like receptors signaling: the unfairly-forgotten.Cell communication and signaling : CCS · 2021Review
- Determinants of Innate Immunity in Visceral Leishmaniasis and Their Implication in Vaccine Development.Frontiers in immunology · 2021Review
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- Interplay Between Sialic Acids, Siglec-E, and Neu1 Regulates MyD88- and TRIF-Dependent Pathways for TLR4-Activation DuringFrontiers in immunology · 2021Article
- The Role of Sialic Acids in the Establishment of Infections by Pathogens, With Special Focus onFrontiers in cellular and infection microbiology · 2021Review
- Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets.International immunopharmacology · 2020Review
- Phosphoproteomic Analysis of Rat Neutrophils Shows the Effect of Intestinal Ischemia/Reperfusion and Preconditioning on Kinases and Phosphatases.International journal of molecular sciences · 2020Article
- Transcriptional analysis of THP-1 cells infected with Leishmania infantum indicates no activation of the inflammasome platform.PLoS neglected tropical diseases · 2020Article
- Article
- Modulation of Host-Pathogen Communication by Extracellular Vesicles (EVs) of the Protozoan ParasiteFrontiers in cellular and infection microbiology · 2019Review
- Ts-Hsp70 induces protective immunity against Trichinella spiralis infection in mouse by activating dendritic cells through TLR2 and TLR4.PLoS neglected tropical diseases · 2018Article
- Review
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Parasites of the Leishmania genus can rapidly alter several macrophage (MØ) signalling pathways in order to tame down the innate immune response and inflammation, therefore favouring their survival and propagation within their mammalian host. Having recently reported that Leishmania and bacterial LPS generate a significantly stronger inflammatory response in animals and phagocytes functionally deficient for the Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), we hypothesized that Leishmania could exploit SHP-1 to inactivate key kinases involved in Toll-like receptor (TLR) signalling and innate immunity such as IL-1 receptor-associated kinase 1 (IRAK-1). Here we show that upon infection, SHP-1 rapidly binds to IRAK-1, completely inactivating its intrinsic kinase activity and any further LPS-mediated activation as well as MØ functions. We also demonstrate that the SHP-1/IRAK-1 interaction occurs via an evolutionarily conserved ITIM-like motif found in the kinase domain of IRAK-1, which we named KTIM (Kinase Tyrosyl-based Inhibitory Motif). This regulatory motif appeared in early vertebrates and is not found in any other IRAK family member. Our study additionally reveals that several other kinases (e.g. Erk1/2, IKKalpha/beta) involved in downstream TLR signalling also bear KTIMs in their kinase domains and interact with SHP-1. We thus provide the first demonstration that a pathogen can exploit a host protein tyrosine phosphatase, namely SHP-1, to directly inactivate IRAK-1 through a generally conserved KTIM motif.
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