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.
Liberati
Nicole T
NT
Department of Genetics, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
Fitzgerald
Katherine A
KA
Kim
Dennis H
DH
Feinbaum
Rhonda
R
Golenbock
Douglas T
DT
Ausubel
Frederick M
FM
D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics / Q000276:immunology*; D017931:DNA Primers; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D017931:DNA Primers; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases