The tyrosine kinase Syk promotes phagocytosis of Francisella through the activation of Erk.
Francisella tularensis is a highly infectious, Gram-negative intra-cellular pathogen that can cause the zoonotic disease tularemia. Although the receptors critical for internalization of Francisella by macrophages are beginning to be defined, the identity of the downstream signaling pathways essential for the engulfment are not yet identified. In this study we have tested the role of Syk in the phagocytosis of Francisella. We report that Syk is activated during Francisella infection and is critical for the uptake of the organisms. Pharmacologic inhibition of Syk almost completely abrogated uptake, whereas the overexpression of Syk significantly enhanced uptake. However, Syk appears to be dispensable during initial host-pathogen contact. Further analyses of the molecular mechanism of Syk influence on Francisella uptake revealed that the MAPK Erk but not the phosphatidylinositol 3 kinase (PI3K)/Akt pathway is the downstream effector of Syk. Thus, the inhibition of Erk in Syk-overexpressing cells or the inhibition of Syk in Erk-overexpressing cells led to a significant attenuation of uptake. Collectively, these data identify Syk and Erk as key players in the phagocytosis of Francisella.
Parsa
Kishore V L
KV
Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
Butchar
Jonathan P
JP
Rajaram
Murugesan V S
MV
Cremer
Thomas J
TJ
Tridandapani
Susheela
S
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005603:Francisella / Q000166:cytology* / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology / Q000382:microbiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3