SARM-Mediated Nuclear Signaling in Innate Immunity

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Cellular signal transduction pathways are essential for maintaining an effective innate immune response to microbes. In some cases, however, inflammation that arises from exposure to microbial products can lead to acute inflammatory syndromes. Toll-like receptors (TLRs) are a family of surface receptors that recognize microbial molecules and initiate intracellular signaling events resulting in upregulation of inflammatory genes. These receptors possess a TIR domain in their cytoplasmic tails that interacts with a TIR domain in intracellular adaptors. The signal is then relayed through a network of downstream signaling events that culminates in a nuclear response specific to the original stimulus. SARM was recently shown to possess a TIR domain as well as another domain, Arm, which is essential for mediating transport of transcription factors through the nuclear pore complex. No data exists on SARM function in humans, however the possession of these two domains suggests SARM may play a role directly linking Toll/IL-1 receptor activation with nuclear import machinery. The knowledge that we hope to obtain about SARM will provide a better understanding of the potential direct link between membrane recognition and nuclear signaling and may indicate a new target for attenuation of inflammation. The function of the SARM protein will be characterized by 1) Screening various TLR signaling pathways for SARM involvement, 2) Determining if SARM is involved in nuclear import of transcription factors, 3) Silencing/overexpression of SARM to further characterize function through analysis of defects in signaling and 4) Determining proteins associated with SARM during basal vs. induced states.