Extracellular signal-regulated kinase activation by Neisseria gonorrhoeae downregulates epithelial cell proapoptotic proteins Bad and Bim.
Neisseria gonorrhoeae expressing type IV pili (Tfp) activates extracellular signal-regulated kinase (ERK) and induces a cytoprotective state in the epithelial cell in a manner that is enhanced by pilT. As the ERK signaling pathway is well-known for its role in cytoprotection and cell survival, we tested the hypothesis that ERK is involved in producing this cytoprotective effect. Inhibiting ERK activation prior to infection attenuated the ability of these bacteria to induce cytoprotection. Activated ERK specifically targeted two proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins, Bim and Bad, for downregulation at the protein level. Bim downregulation occurred through the proteasome. ERK, in addition, inactivated Bad by triggering its phosphorylation at Ser112. Finally, reducing the level of either Bad or Bim alone by small interfering RNA was sufficient to protect uninfected cells from staurosporine-induced apoptosis. We conclude that Tfp-induced cytoprotection is due in part to ERK-dependent modification and/or downregulation of proapoptotic proteins Bad and Bim.
Howie
Heather L
HL
Department of Molecular Microbiology & Immunology, L220, Oregon Health and Science University, Portland, Oregon 97201, USA.
Shiflett
Shelly L
SL
So
Magdalene
M
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009344:Neisseria gonorrhoeae / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051025:bcl-Associated Death Protein / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; D048049:Extracellular Signal-Regulated MAP Kinases