Trxlp, a thioredoxin-like effector from Edwardsiella piscicida inhibits cellular redox signaling and nuclear translocation of NF-κB

TY - JOUR

T1 - Trxlp, a thioredoxin-like effector from Edwardsiella piscicida inhibits cellular redox signaling and nuclear translocation of NF-κB

AU - Sayed, Ahmed

AU - Chakraborty, Smarajit

AU - Leung, Ka Yin

AU - Sugii, Shigeki

AU - Mok, Yu Keung

N1 - Publisher Copyright: © 2020 Elsevier B.V.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Redox signaling and homeostasis are essential for cell survival and the immune response. Peroxiredoxin (Prx) modulates the level of H2O2 as a redox signal through H2O2 decomposition. The redox activity of thioredoxin (Trx) is required as a reducing equivalent to regenerate Prx. Edwardsiella piscicida is an opportunistic Gram-negative enteric pathogen that secretes a novel Trx-like effector protein, ETAE_2186 (Trxlp). Trxlp has unique structural properties compared with other Trx proteins. In enzymatic and binding assays, we confirmed Trxlp to be redox-inactive due to the low reactivity and flexibility of the resolving cysteine residue, C35, at the active site motif “31WCXXC35”. We identified key residues near the active site that are critical for reactivity and flexibility of C35 by site-directed mutagenesis analysis. NMR titration experiment demonstrated prolong inhibitory interaction of Trxlp with Prx1 resulting in the repression of Prx1–mediated H2O2 decomposition leading to increased ROS accumulation in infected host cells. Increased ROS in turn prevented nuclear translocation of NF-κB and inhibition of NF-κB target genes, leading to bacterial survival and enhanced replication inside host cells. Targeting Trxlp-mediated virulence promises to attenuate E. piscicida infection.

AB - Redox signaling and homeostasis are essential for cell survival and the immune response. Peroxiredoxin (Prx) modulates the level of H2O2 as a redox signal through H2O2 decomposition. The redox activity of thioredoxin (Trx) is required as a reducing equivalent to regenerate Prx. Edwardsiella piscicida is an opportunistic Gram-negative enteric pathogen that secretes a novel Trx-like effector protein, ETAE_2186 (Trxlp). Trxlp has unique structural properties compared with other Trx proteins. In enzymatic and binding assays, we confirmed Trxlp to be redox-inactive due to the low reactivity and flexibility of the resolving cysteine residue, C35, at the active site motif “31WCXXC35”. We identified key residues near the active site that are critical for reactivity and flexibility of C35 by site-directed mutagenesis analysis. NMR titration experiment demonstrated prolong inhibitory interaction of Trxlp with Prx1 resulting in the repression of Prx1–mediated H2O2 decomposition leading to increased ROS accumulation in infected host cells. Increased ROS in turn prevented nuclear translocation of NF-κB and inhibition of NF-κB target genes, leading to bacterial survival and enhanced replication inside host cells. Targeting Trxlp-mediated virulence promises to attenuate E. piscicida infection.

KW - Peroxiredoxin

KW - Redox signaling

KW - Thioredoxin-like effector

UR - http://www.scopus.com/inward/record.url?scp=85077913022&partnerID=8YFLogxK

U2 - 10.1016/j.ijbiomac.2020.01.114

DO - 10.1016/j.ijbiomac.2020.01.114

M3 - 文章

C2 - 31945434

AN - SCOPUS:85077913022

SN - 0141-8130

VL - 148

SP - 89

EP - 101

JO - International Journal of Biological Macromolecules

JF - International Journal of Biological Macromolecules

ER -