Brucella TIR Domain-containing Protein Mimics Properties of the Toll-like Receptor Adaptor Protein TIRAP

• Published in: The Journal of biological chemistry Vol. 284; no. 15; pp. 9892 - 9898
• Main Authors: Radhakrishnan, Girish K., Yu, Qiqi, Harms, Jerome S., Splitter, Gary A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2009; American Society for Biochemistry and Molecular Biology
• Subjects: adaptor proteins; Amino Acid Sequence; Animals; Bacterial Proteins - chemistry; Bacterial Proteins - physiology; Brucella; Brucella - metabolism; Cell Line; Cytoskeleton; Cytoskeleton - metabolism; HeLa Cells; Humans; Immune response; Infection; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - physiology; Mice; Microorganisms; Molecular Sequence Data; MyD88 protein; NF-B protein; NF-kappa B - metabolism; Phosphatidylinositols - chemistry; phosphoinositides; Plasma membranes; Protein Structure, Tertiary; Receptors, Interleukin-1 - chemistry; Receptors, Interleukin-1 - physiology; Sequence Homology, Amino Acid; Signal transduction; Survival; Toll-like receptors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M805458200

Toll-like receptors (TLRs) play essential roles in the activation of innate immune responses against microbial infections. TLRs and downstream adaptor molecules contain a conserved cytoplasmic TIR domain. TIRAP is a TIR domain-containing adaptor protein that recruits the signaling adaptor MyD88 to a subset of TLRs. Many pathogenic microorganisms subvert TLR signaling pathways to suppress host immune responses to benefit their survival and persistence. Brucella encodes a TIR domain-containing protein (TcpB) that inhibits TLR2- and TLR4-mediated NF-κB activation. Sequence analysis indicated a moderate level of similarity between TcpB and the TLR adaptor molecule TIRAP. We found that TcpB could efficiently block TIRAP-induced NF-κB activation. Subsequent studies revealed that by analogy to TIRAP, TcpB interacts with phosphoinositides through its N-terminal domain and colocalizes with the plasma membrane and components of the cytoskeleton. Our findings suggest that TcpB targets the TIRAP-mediated pathway to subvert TLR signaling. In vivo mouse studies indicated that TcpB-deficient Brucella is defective in systemic spread at the early stages of infection.