A filarial nematode-secreted phosphorylcholine-containing glycoprotein uncouples the B cell antigen receptor from extracellular signal-regulated kinase-mitogen-activated protein kinase by promoting the surface Ig-mediated recruitment of Src homology 2 domain-containing tyrosine phosphatase-1 and Pac-1 mitogen-activated kinase-phosphatase.
Unraveling the molecular mechanisms by which filarial nematodes, major human pathogens in the tropics, evade the host immune system remains an elusive goal. We have previously shown that excretory-secretory product-62 (ES-62), a homologue of phosphorylcholine-containing molecules that are secreted by human parasites and which is active in rodent models of filarial infection, is able to polyclonally activate certain protein tyrosine kinase and mitogen-activating protein kinase signal transduction elements in B lymphocytes. Such activation mediates desensitization of subsequent B cell Ag receptor (BCR) ligation-induced activation of extracellular signal-regulated kinase-mitogen-activated protein (ErkMAP) kinase and ultimately B cell proliferation. We now show that the desensitization is due to ES-62 targeting two major regulatory sites of B cell activation. Firstly, pre-exposure to ES-62 primes subsequent BCR-mediated recruitment of SHP-1 tyrosine phosphatase to abolish recruitment of the RasErkMAP kinase cascade via the Igalphabeta-ShcGrb2Sos adaptor complex interactions. Secondly, any ongoing ErkMAP kinase signaling in ES-62-primed B cells is terminated by the MAP kinase phosphatase, Pac-1 that is activated consequently to challenge via the BCR.
Deehan
M R
MR
Department of Immunology, University of Glasgow, Glasgow, United Kingdom.
Harnett
W
W
Harnett
M M
MM
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000947:Antigens, Helminth / Q000276:immunology; D051925:CD79 Antigens; D004153:Dipetalonema / Q000276:immunology*; D054641:Dual Specificity Phosphatase 2; D004789:Enzyme Activation / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D015801:Helminth Proteins / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000276:immunology*; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism* / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; D000947:Antigens, Helminth; D051925:CD79 Antigens; C497884:Cd79b protein, mouse; D006023:Glycoproteins; D015801:Helminth Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D010767:Phosphorylcholine; D014443:Tyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; C517033:Dusp2 protein, mouse; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse