Research Article: The Edwardsiella piscicida thioredoxin-like protein inhibits ASK1-MAPKs signaling cascades to promote pathogenesis during infection

Date Published: July 17, 2019

Publisher: Public Library of Science

Author(s): Dahai Yang, Xiaohong Liu, Wenting Xu, Zhaoyan Gu, Cuiting Yang, Lingzhi Zhang, Jinchao Tan, Xin Zheng, Zhuang Wang, Shu Quan, Yuanxing Zhang, Qin Liu, Zhao-Qing Luo.


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.

Partial Text

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]. In mammalian cells, interactions between cytosolic TRX1 and apoptosis signal-regulating kinase 1 (ASK1) suppress the activation of c-Jun N-terminal kinase (JNK)-, Erk1/2-, and p38-MAPK signaling cascades in response to various stress stimuli and activate a number of transcription factors that regulate various aspects of cell growth and survival [2–8].

Trx was originally considered an important conserved family for protection against ROS by reducing peroxides to harmless products [7–8]. The antioxidant defense system of microorganisms comprises various conserved antioxidant molecules [8], but little is known about the specific roles of these molecules during infection. In this study, we analyzed all annotated Trx family proteins of E. piscicida, and found that only Trxlp was significantly upregulated when compared with the levels of classical bacterial Trx family proteins during infection (Figs 1A and S1). However, this Trxlp showed significantly lower redox activity than the classical reducing Trxs in EIB202 (S3 Fig). This is the first report that a unique bacterial thioredoxin was utilized as a virulence effector to interfere with host antibacterial signaling, which expands our understanding of the bacterial Trx family proteins that not only catalyze protein disulfide reductase, but also function as virulence effectors during infection.




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