Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL.
Gram-negative bacteria belonging to the Brucella species cause chronic infections that can result in undulant fever, arthritis, and osteomyelitis in humans. Remarkably, Brucella sp. genomes encode a protein, named TcpB, that bears significant homology with mammalian Toll/IL-1 receptor domains and whose expression causes degradation of the phosphorylated, signal competent form of the adapter MyD88-adapter-like (MAL). This effect of TcpB is mediated through its box 1 region and has no effect on other TLR adapter proteins such as MyD88 or TIR-domain containing adapter protein-inducing IFNbeta. TcpB also does not affect a mutant, signal-incompetent form of MAL that cannot be phosphorylated. Interestingly, the presence of TcpB leads to enhanced polyubiquitination of MAL, which is likely responsible for its accelerated degradation. A Brucella abortus mutant lacking TcpB fails to reduce levels of MAL in infected macrophages. Therefore, TcpB represents a unique pathogen-derived molecule that suppresses host innate-immune responses by specifically targeting an individual adapter molecule in the TLR signaling pathway for degradation.
Sengupta
Dola
D
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Koblansky
Alicia
A
Gaines
Jennifer
J
Brown
Tim
T
West
A Phillip
AP
Zhang
Dekai
D
Nishikawa
Tak
T
Park
Sung-Gyoo
SG
Roop
R Martin
RM
Ghosh
Sankar
S
D002002:Brucella / Q000472:pathogenicity*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D025801:Ubiquitin; D014764:Viral Proteins / Q000502:physiology
D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D025801:Ubiquitin; D014764:Viral Proteins