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

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.

Pubmed ID: 15123841


  • Liberati NT
  • Fitzgerald KA
  • Kim DH
  • Feinbaum R
  • Golenbock DT
  • Ausubel FM


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

April 27, 2004

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI52455
  • Agency: NIGMS NIH HHS, Id: GM48707

Mesh Terms

  • Animals
  • Base Sequence
  • Caenorhabditis elegans
  • DNA Primers
  • Enzyme Activation
  • Gene Expression Regulation
  • Membrane Glycoproteins
  • Mitogen-Activated Protein Kinases
  • Receptors, Interleukin-1
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases