Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases.
With more than 12 million people affected worldwide, 2 million new cases occurring per year, and the rapid emergence of drug resistance and treatment failure, leishmaniasis is an infectious disease for which research on drug and vaccine development, host-pathogen, and vector-parasite interactions are current international priorities. Upon Leishmania-macrophage interaction, activation of the protein tyrosine phosphatase (PTP) SHP-1 rapidly leads to the down-regulation of Janus kinase and mitogen-activated protein kinase signaling, resulting in the attenuation of host innate inflammatory responses and of various microbicidal macrophage functions. We report that, in addition to SHP-1, the PTPs PTP1B and TCPTP are activated and posttranslationally modified in infected macrophages, and we identify an essential role for PTP1B in the in vivo progression of Leishmania infection. The mechanism underlying PTP modulation involves the proteolytic activity of the Leishmania surface protease GP63. Access of GP63 to macrophage PTP1B, TCPTP, and SHP-1 is mediated in part by a lipid raft-dependent mechanism, resulting in PTP cleavage and stimulation of phosphatase activity. Collectively, our data present a mechanism of cleavage-dependent activation of macrophage PTPs by an obligate intracellular pathogen and show that internalization of GP63, a key Leishmania virulence factor, into host macrophages is a strategy the parasite uses to interact and survive within its host.
Department of Experimental Medicine, McGill University, Montréal, Québec, Canada.
Maria Adelaida
MA
Gomez
Irazu
I
Contreras
Maxime
M
Hallé
Michel L
ML
Tremblay
Robert W
RW
McMaster
Martin
M
Olivier
D000818:Animals; D002460:Cell Line; D006790:Host-Parasite Interactions / Q000502:physiology; D006801:Humans; D018320:Leishmania major / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D007896:Leishmaniasis / Q000469:parasitology / Q000503:physiopathology; D008264:Macrophages / Q000469:parasitology / Q000502:physiology; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000502:physiology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D015800:Protozoan Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D015800:Protozoan Proteins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; C509248:Ptpn6 protein, mouse; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania