title: Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL.
abstract: 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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Dola
authors.initials: D
authors.lastname: Sengupta
authors.forename: Alicia
authors.initials: A
authors.lastname: Koblansky
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gaines
authors.forename: Tim
authors.initials: T
authors.lastname: Brown
authors.forename: A Phillip
authors.initials: AP
authors.lastname: West
authors.forename: Dekai
authors.initials: D
authors.lastname: Zhang
authors.forename: Tak
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Sung-Gyoo
authors.initials: SG
authors.lastname: Park
authors.forename: R Martin
authors.initials: RM
authors.lastname: Roop
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
mesh_terms: 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
chemical_list: 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