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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.

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Related in: MedlinePlus

Evolution of vertebrate IRAK-1 and SHP-1 from IRAK-4 and SHP-2 ancestor genes.Schematic representation of the appearance of IRAK-1 and SHP-1 from gene duplication events of the IRAK-4 (A) and SHP-2 (B) ancestor genes, respectively. The emergence of the KTIM in IRAK-1 occurred after this gene duplication event took place as the motif only appeared in amphibians. Similarity percentages were calculated using the mouse IRAK-1 and IRAK-4 sequences.
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pntd-0000305-g009: Evolution of vertebrate IRAK-1 and SHP-1 from IRAK-4 and SHP-2 ancestor genes.Schematic representation of the appearance of IRAK-1 and SHP-1 from gene duplication events of the IRAK-4 (A) and SHP-2 (B) ancestor genes, respectively. The emergence of the KTIM in IRAK-1 occurred after this gene duplication event took place as the motif only appeared in amphibians. Similarity percentages were calculated using the mouse IRAK-1 and IRAK-4 sequences.

Mentions: Given the important regulatory function of the KTIM present within IRAK-1, we speculated that it would be evolutionarily conserved. In silico sequence comparisons of available IRAK-1 sequences revealed that KTIM (LVYGFL) was fully conserved from rodents to human (Figure 8). However, while the KTIM in Xenopus tropicalis showed some variations compared to the other vertebrate sequences (LIYLYL), it was absent in zebrafish due to the presence of a methionine at the last position (VIYVYM). Next, we addressed the origin of IRAK-1 and SHP-1 as they are only present in vertebrates. Sequence similarity analyses, including available IRAK-4 sequences from vertebrates and invertebrates (Figure S4), indicate that IRAK-1 evolved from IRAK-4 by gene duplication (Figure 9A). Similar sequence similarity comparisons suggest that SHP-1 evolved from SHP-2 and its orthologues found in invertebrates and that the ancestral SHP-1 gene also appeared through gene duplication in lower vertebrates (zebrafish) (Figure 9B).


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)

Evolution of vertebrate IRAK-1 and SHP-1 from IRAK-4 and SHP-2 ancestor genes.Schematic representation of the appearance of IRAK-1 and SHP-1 from gene duplication events of the IRAK-4 (A) and SHP-2 (B) ancestor genes, respectively. The emergence of the KTIM in IRAK-1 occurred after this gene duplication event took place as the motif only appeared in amphibians. Similarity percentages were calculated using the mouse IRAK-1 and IRAK-4 sequences.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0000305-g009: Evolution of vertebrate IRAK-1 and SHP-1 from IRAK-4 and SHP-2 ancestor genes.Schematic representation of the appearance of IRAK-1 and SHP-1 from gene duplication events of the IRAK-4 (A) and SHP-2 (B) ancestor genes, respectively. The emergence of the KTIM in IRAK-1 occurred after this gene duplication event took place as the motif only appeared in amphibians. Similarity percentages were calculated using the mouse IRAK-1 and IRAK-4 sequences.
Mentions: Given the important regulatory function of the KTIM present within IRAK-1, we speculated that it would be evolutionarily conserved. In silico sequence comparisons of available IRAK-1 sequences revealed that KTIM (LVYGFL) was fully conserved from rodents to human (Figure 8). However, while the KTIM in Xenopus tropicalis showed some variations compared to the other vertebrate sequences (LIYLYL), it was absent in zebrafish due to the presence of a methionine at the last position (VIYVYM). Next, we addressed the origin of IRAK-1 and SHP-1 as they are only present in vertebrates. Sequence similarity analyses, including available IRAK-4 sequences from vertebrates and invertebrates (Figure S4), indicate that IRAK-1 evolved from IRAK-4 by gene duplication (Figure 9A). Similar sequence similarity comparisons suggest that SHP-1 evolved from SHP-2 and its orthologues found in invertebrates and that the ancestral SHP-1 gene also appeared through gene duplication in lower vertebrates (zebrafish) (Figure 9B).

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