ACTIVATION OF ERK/MAPK SIGNALING BY BURKHOLDERIA PSEUDOMALLEI CYCLE INHIBITING FACTOR

Abstract

Cycle inhibiting factors (Cifs) are virulence proteins secreted by the T3SS of some Gram-negative pathogenic bacteria including Burkholderia pseudomallei. Cif is known to function to deamidate Nedd8, leading to inhibition of Cullin E3 ubiquitin ligases (CRL) and consequently induction of cell cycle arrest. Here I show that Cif functions as a potent activator of MAPK/ERK signaling, and this is dependent on its deamidase activity, but independent of Cullin E3 ligase inhibition. I provide evidence that the mechanism involved is dependent on recruitment of the Grb2-SOS1 complex to the plasma membrane, and that Cif modifies the phosphorylation status of SOS1 in the CDC25-H and proline-rich domains. Since prolonged Cullin E3 ligase inhibition is known to lead to cellular apoptosis, I hypothesise that ERK activation functions to counter the pro-apoptotic effects of Cif. Indeed, I show that Cif-dependent ERK activation promotes phosphorylation of the pro-apoptotic protein Bim, thereby conferring a pro-survival signal.