Liberati, Nicole T.Fitzgerald, Katherine A.Kim, Dennis H.Feinbaum, RhondaGolenbock, Douglas T.Ausubel, Frederick M.2019-10-122004Liberati, N. T., K. A. Fitzgerald, D. H. Kim, R. Feinbaum, D. T. Golenbock, and F. M. Ausubel. 2004. “Requirement for a Conserved Toll/Interleukin-1 Resistance Domain Protein in the Caenorhabditis Elegans Immune Response.” Proceedings of the National Academy of Sciences101 (17): 6593–98. doi:10.1073/pnas.0308625101.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41542728The 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/lL-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.en-USJournal Article2019-10-1210.1073/pnas.0308625101