Limits...
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif.

Abu-Dayyeh I, Shio MT, Sato S, Akira S, Cousineau B, Olivier M - PLoS Negl Trop Dis (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.

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.

Show MeSH

Related in: MedlinePlus

Inhibition of LPS-mediated functions by Leishmania.(A) LPS-mediated MØ IL-12 mRNA expression was analyzed by RT-PCR in uninfected and Leishmania-infected MØs. Cells were infected with L. donovani O/N followed by LPS stimulation (10 and 100 ng/ml, 12 h). (B) LPS-mediated TNF production by MØs infected with Leishmania. Cells have been infected as above and stimulated with LPS for 3 h. (C) NO production by Leishmania-infected MØs in response to LPS. Cells have been infected as above and stimulated with LPS for 24 h. (A–C) *, significant at P<0.05, Anova test, error bar SEM. Mean of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2596967&req=5

pntd-0000305-g005: Inhibition of LPS-mediated functions by Leishmania.(A) LPS-mediated MØ IL-12 mRNA expression was analyzed by RT-PCR in uninfected and Leishmania-infected MØs. Cells were infected with L. donovani O/N followed by LPS stimulation (10 and 100 ng/ml, 12 h). (B) LPS-mediated TNF production by MØs infected with Leishmania. Cells have been infected as above and stimulated with LPS for 3 h. (C) NO production by Leishmania-infected MØs in response to LPS. Cells have been infected as above and stimulated with LPS for 24 h. (A–C) *, significant at P<0.05, Anova test, error bar SEM. Mean of three independent experiments.

Mentions: Using Leishmania as an infectious model, we studied its ability to inhibit key MØ LPS-mediated functions namely: IL-12 expression, TNF production, and NO generation. Our results confirmed that infection with Leishmania caused a significant inhibition of LPS-mediated expression of IL-12 (Figure 5A), TNF production (Figure 5B), and NO generation (Figure 5C) in MØs.


Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif.

Abu-Dayyeh I, Shio MT, Sato S, Akira S, Cousineau B, Olivier M - PLoS Negl Trop Dis (2008)

Inhibition of LPS-mediated functions by Leishmania.(A) LPS-mediated MØ IL-12 mRNA expression was analyzed by RT-PCR in uninfected and Leishmania-infected MØs. Cells were infected with L. donovani O/N followed by LPS stimulation (10 and 100 ng/ml, 12 h). (B) LPS-mediated TNF production by MØs infected with Leishmania. Cells have been infected as above and stimulated with LPS for 3 h. (C) NO production by Leishmania-infected MØs in response to LPS. Cells have been infected as above and stimulated with LPS for 24 h. (A–C) *, significant at P<0.05, Anova test, error bar SEM. Mean of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2596967&req=5

pntd-0000305-g005: Inhibition of LPS-mediated functions by Leishmania.(A) LPS-mediated MØ IL-12 mRNA expression was analyzed by RT-PCR in uninfected and Leishmania-infected MØs. Cells were infected with L. donovani O/N followed by LPS stimulation (10 and 100 ng/ml, 12 h). (B) LPS-mediated TNF production by MØs infected with Leishmania. Cells have been infected as above and stimulated with LPS for 3 h. (C) NO production by Leishmania-infected MØs in response to LPS. Cells have been infected as above and stimulated with LPS for 24 h. (A–C) *, significant at P<0.05, Anova test, error bar SEM. Mean of three independent experiments.
Mentions: Using Leishmania as an infectious model, we studied its ability to inhibit key MØ LPS-mediated functions namely: IL-12 expression, TNF production, and NO generation. Our results confirmed that infection with Leishmania caused a significant inhibition of LPS-mediated expression of IL-12 (Figure 5A), TNF production (Figure 5B), and NO generation (Figure 5C) in MØs.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.

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.

Show MeSH
Related in: MedlinePlus