Dynamic regulation of neutrophil survival through tyrosine phosphorylation or dephosphorylation of caspase-8.
Efficient expression of innate immunity is critically dependent upon the capacity of the neutrophil to be activated rapidly in the face of an acute threat and to involute once that threat has been eliminated. Here we report a novel mechanism regulating neutrophil survival dynamically through the tyrosine phosphorylation or dephosphorylation of caspase-8. Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. SHP-1 activity is reduced and Lyn increased in neutrophils from patients with sepsis, in association with profoundly delayed apoptosis; inhibition of Lyn can partially reverse this delay. Thus the phosphorylation and dephosphorylation of caspase-8, mediated by Lyn and SHP-1, respectively, represents a novel, dynamic post-translational mechanism for the regulation of neutrophil apoptosis whose dysregulation contributes to persistent neutrophil survival in sepsis.
Jia
Song Hui
SH
Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Parodo
Jean
J
Kapus
Andras
A
Rotstein
Ori D
OD
Marshall
John C
JC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016466:CHO Cells; D053181:Caspase 8 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
D008070:Lipopolysaccharides; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D053181:Caspase 8