Date Published: December 23, 2008
Publisher: Public Library of Science
Author(s): Issa Abu-Dayyeh, Marina Tiemi Shio, Shintaro Sato, Shizuo Akira, Benoit Cousineau, Martin Olivier, Peter J. Hotez
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, IKKα/β) 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.
Partial Text: Innate inflammatory responses play a critical role in controlling pathogens . However, protozoan parasites such as Leishmania evolved strategies to avoid phagocyte activation by seizing control of key signalling pathways, therefore favouring their invasion and survival within the host cell . We recently reported that the protein tyrosine phosphatase (PTP) SHP-1 plays a pivotal role in taming down phagocyte-mediated inflammatory responses . For instance, we showed that in the absence of SHP-1, several pro-inflammatory cytokines (e.g. IL-1β, IL-6, TNFα) and chemokines, as well as inflammatory neutrophil recruitment were all exacerbated by Leishmania infection . Of interest, we also found that LPS mediates an excessive inflammatory response in the absence of SHP-1, therefore suggesting that SHP-1 could exert its negative regulatory action via Toll like receptor (TLR) signalling.
Leishmania has been reported to inhibit critical LPS-mediated MØ functions such as NO and pro-inflammatory cytokines (e.g. IL-12 and TNF) production ,,. Although mechanisms whereby NO is inhibited by Leishmania in response to IFN-γ have been well explored , our knowledge concerning the negative regulatory mechanisms leading to the down-regulation of LPS-mediated MØ functions in Leishmania-infected cells is limited. Herein, we provide the first demonstration that the Leishmania parasite can rapidly inactivate IRAK-1 kinase activity with the participation of SHP-1, therefore inhibiting MØ LPS-mediated functions. We further reveal that the mechanism by which this inactivation occurs is through the binding of SHP-1 to an evolutionarily-conserved ITIM-like motif located in the kinase domain of IRAK-1. This is the first demonstration that a pathogen can use a host PTP to inactivate IRAK-1 and therefore block signalling pathways ultimately leading to free radicals and pro-inflammatory cytokines production known to be detrimental to its survival.