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Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6593-8.

Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response.

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1
Department of Genetics, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

The p38 mitogen-activated protein kinase pathway regulates innate immune responses in evolutionarily diverse species. We have previously shown that the Caenorhabditis elegans p38 mitogen-activated protein kinase, PMK-1, functions in an innate immune response pathway that mediates resistance to a variety of microbial pathogens. Here, we show that tir-1, a gene encoding a highly conserved Toll/IL-1 resistance (TIR) domain protein, is also required for C. elegans resistance to microbial pathogens. RNA interference inactivation of tir-1 resulted in enhanced susceptibility to killing by pathogens and correspondingly diminished PMK-1 phosphorylation. Unlike all known TIR-domain adapter proteins, overexpression of the human TIR-1 homologue, SARM, in mammalian cells was not sufficient to induce expression of NF-kappaB or IRF3-dependent reporter genes that are activated by Toll-like receptor signaling. These data reveal the involvement of a previously uncharacterized, evolutionarily conserved TIR domain protein in innate immunity that is functionally distinct from other known TIR domain signaling adapters.

PMID:
15123841
PMCID:
PMC404090
DOI:
10.1073/pnas.0308625101
[Indexed for MEDLINE]
Free PMC Article
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