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PMID: 20018612 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 184 ·No. 2 ·2010-01-15 ·Pages 956-64

Sengupta D, Koblansky A, Gaines J, Brown T, West AP, Zhang D, Nishikawa T, Park SG, Roop RM, Ghosh S

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.

MeSH Terms
Brucella/pathogenicity Cell Line Humans Immunity, Innate Membrane Glycoproteins/metabolism Phosphorylation Receptors, Interleukin-1/metabolism Sequence Homology, Amino Acid Toll-Like Receptor 4/metabolism Ubiquitin Viral Proteins/physiology
Chemicals
Membrane Glycoproteins Receptors, Interleukin-1 TIRAP protein, human TLR4 protein, human Toll-Like Receptor 4 Ubiquitin Viral Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sengupta Dola
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Koblansky Alicia
Gaines Jennifer
Brown Tim
West A Phillip
Zhang Dekai
Nishikawa Tak
Park Sung-Gyoo
Roop R Martin
Ghosh Sankar
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0902008
Published
2010-01-15
Epub
2009-00-14
Pages
956-64
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC3644118
Subset
IM
Grants
NIAID NIH HHS · R01-AI059440 · United States
NIAID NIH HHS · R21-AI63373 · United States
NIAID NIH HHS · R37 AI033443 · United States
NIAID NIH HHS · R01 AI059440 · United States
NIAID NIH HHS · R37-AI33443 · United States
NIAID NIH HHS · R21 AI063373 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0902008 PMC Full Text View journal details
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