Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif.
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 LP...
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ftdoajarticles:oai:doaj.org/article:16b46c5be2b441848f2ece0df8e2f598 2023-05-15T15:11:13+02:00 Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. Issa Abu-Dayyeh Marina Tiemi Shio Shintaro Sato Shizuo Akira Benoit Cousineau Martin Olivier 2008-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000305 https://doaj.org/article/16b46c5be2b441848f2ece0df8e2f598 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2596967?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000305 https://doaj.org/article/16b46c5be2b441848f2ece0df8e2f598 PLoS Neglected Tropical Diseases, Vol 2, Iss 12, p e305 (2008) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2008 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000305 2022-12-31T12:17:47Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 2 12 e305 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Issa Abu-Dayyeh Marina Tiemi Shio Shintaro Sato Shizuo Akira Benoit Cousineau Martin Olivier Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Issa Abu-Dayyeh Marina Tiemi Shio Shintaro Sato Shizuo Akira Benoit Cousineau Martin Olivier |
author_facet |
Issa Abu-Dayyeh Marina Tiemi Shio Shintaro Sato Shizuo Akira Benoit Cousineau Martin Olivier |
author_sort |
Issa Abu-Dayyeh |
title |
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. |
title_short |
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. |
title_full |
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. |
title_fullStr |
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. |
title_full_unstemmed |
Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. |
title_sort |
leishmania-induced irak-1 inactivation is mediated by shp-1 interacting with an evolutionarily conserved ktim motif. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2008 |
url |
https://doi.org/10.1371/journal.pntd.0000305 https://doaj.org/article/16b46c5be2b441848f2ece0df8e2f598 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 2, Iss 12, p e305 (2008) |
op_relation |
http://europepmc.org/articles/PMC2596967?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0000305 https://doaj.org/article/16b46c5be2b441848f2ece0df8e2f598 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000305 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
2 |
container_issue |
12 |
container_start_page |
e305 |
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1766342111230164992 |