A Burkholderia pseudomallei Toxin Inhibits Helicase Activity of Translation Factor eIF4A

Abstract

The structure of BPSL1549, a protein of unknown function from Burkholderia pseudomallei, reveals a similarity to Escherichia coli cytotoxic necrotizing factor 1. We found that BPSL1549 acted as a potent cytotoxin against eukaryotic cells and was lethal when administered to mice. Expression levels of bpsl1549 correlate with conditions expected to promote or suppress pathogenicity. BPSL1549 promotes deamidation of glutamine-339 of the translation initiation factor eIF4A, abolishing its helicase activity and inhibiting translation. We propose to name BPSL1549 Burkholderia lethal factor 1.

Dissecting novel virulent determinants in theBurkholderia cepaciacomplex

“…Recent examples include a Bcc toxin that is hemolytic and required for full virulence 40 and a B. pseudomallei toxin, named Burkholderia lethal factor 1. 41 Using transposon mutagenesis, Thomson et al 40 identified a Bcc gene cluster capable of expressing a toxin that is a broad-specificity hemolysin required for full Bcc virulence. Functionally related to the previously identified antifungal compound burkholdine or occidiofungin, the Bcc toxin is synthesized via a nonribosomal peptide synthetase (NRPS) mechanism, and mutations in this gene cluster cause a significant reduction in both hemolysis and G. mellonella mortality.…”

“…41 It is a potent cytotoxin against eukaryotic cells and lethal when administered to mice via the intraperitoneal route. The toxin acts on translation initiation factor eI4A and abolishes its helicase activity, thereby inhibiting translation.…”

What a Difference a Dalton Makes: Bacterial Virulence Factors Modulate Eukaryotic Host Cell Signaling Systems via Deamidation

“…BLF1 interacts with the human translation factor eIF4A in human cell lysates (11), suggesting that BLF1 might inhibit translation. This interaction was confirmed by coimmunoprecipitation.…”

“…Reorganization of the actin cytoskeleton is one mechanism used by invasive bacteria to promote entry into host cells (9,10). BLF1 is a toxin from Burkholderia pseudomallei that is lethal to mice and tissue culture cells (11). BLF1 inhibits host protein synthesis via deamidation of eIF4A (11).…”

“…BLF1 is a toxin from Burkholderia pseudomallei that is lethal to mice and tissue culture cells (11). BLF1 inhibits host protein synthesis via deamidation of eIF4A (11). VopC is a type III effector from Vibrio parahaemolyticus that deamidates and constitutively activates small GTPases (12).…”