In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 3 ( 2021-3-31), p. e1009481-
Kurzfassung:
TcpC is a virulence factor of uropathogenic E . coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.
Materialart:
Online-Ressource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009481
DOI:
10.1371/journal.ppat.1009481.g001
DOI:
10.1371/journal.ppat.1009481.g002
DOI:
10.1371/journal.ppat.1009481.g003
DOI:
10.1371/journal.ppat.1009481.g004
DOI:
10.1371/journal.ppat.1009481.g005
DOI:
10.1371/journal.ppat.1009481.g006
DOI:
10.1371/journal.ppat.1009481.g007
DOI:
10.1371/journal.ppat.1009481.g008
DOI:
10.1371/journal.ppat.1009481.t001
DOI:
10.1371/journal.ppat.1009481.s001
DOI:
10.1371/journal.ppat.1009481.s002
DOI:
10.1371/journal.ppat.1009481.s003
DOI:
10.1371/journal.ppat.1009481.s004
DOI:
10.1371/journal.ppat.1009481.s005
DOI:
10.1371/journal.ppat.1009481.s006
DOI:
10.1371/journal.ppat.1009481.s007
DOI:
10.1371/journal.ppat.1009481.s008
DOI:
10.1371/journal.ppat.1009481.s009
DOI:
10.1371/journal.ppat.1009481.s010
DOI:
10.1371/journal.ppat.1009481.s011
DOI:
10.1371/journal.ppat.1009481.s012
DOI:
10.1371/journal.ppat.1009481.s013
DOI:
10.1371/journal.ppat.1009481.r001
DOI:
10.1371/journal.ppat.1009481.r002
DOI:
10.1371/journal.ppat.1009481.r003
DOI:
10.1371/journal.ppat.1009481.r004
DOI:
10.1371/journal.ppat.1009481.r005
DOI:
10.1371/journal.ppat.1009481.r006
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2021
ZDB Id:
2205412-1