Abstract
It is important that bacterium can coordinately deliver several effectors into host cells to disturb the cellular progress during infection, however, the precise role of effectors in host cell cytosol remains to be resolved. In this study, we identified a new bacterial virulence effector from pathogenic Edwardsiella piscicida, which presents conserved crystal structure to thioredoxin family members and is defined as a thioredoxin-like protein (Trxlp). Unlike the classical bacterial thioredoxins, Trxlp can be translocated into host cells, mimicking endogenous thioredoxin to abrogate ASK1 homophilic interaction and phosphorylation, then suppressing the phosphorylation of downstream Erk1/2- and p38-MAPK signaling cascades. Moreover, Trxlp-mediated inhibition of ASK1-Erk/p38-MAPK axis promotes the pathogenesis of E. piscicida in zebrafish larvae infection model. Taken together, these data provide insights into the mechanism underlying the bacterial thioredoxin as a virulence effector in downmodulating the innate immune responses during E. piscicida infection.
Highlights
Thioredoxins (Trxs) are small redox-active molecules ubiquitously expressed in all taxa, from bacteria to mammals, containing a conserved redox catalytic CXXC (-Cys-X-X-Cys-)-motif that links the second β-strand to the second α-helix [1]
We uncover a bacterial thioredoxin-like protein that can be translocated into host cells and mimic the endogenous TRX1 to target apoptosis signal-regulating kinase 1 (ASK1)-Mitogen-activated protein kinase (MAPK) signaling, facilitating bacterial pathogenesis
This work expands our understanding of bacterial thioredoxins in manipulating host innate immunity
Summary
Thioredoxins (Trxs) are small redox-active molecules ubiquitously expressed in all taxa, from bacteria to mammals, containing a conserved redox catalytic CXXC (-Cys-X-X-Cys-)-motif that links the second β-strand to the second α-helix [1]. Bacteria have developed several strategies to target MAPK pathway in order to subvert their functions, one of which is that bacterial virulence factors operate as mimics of host proteins [10,11]. YopJ from Yersinia pestis [13,14] and AvrA from Salmonella [15] was proved function as acetyl transferases that covalently modify key serine and threonine residues of MAPKs, regulating the transcription of pro-survival genes during infection. OspF from Shigella flexneri, which is homologous to the Salmonella SpvC and Pseudomonas syringae HopAI1, possesses the phosphor-threonine lyase activity, and irreversible dephosphorylate MAPKs by covalent modification and inhibit the inflammatory responses [16,17]
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