Alternative titles; symbols
HGNC Approved Gene Symbol: SARM1
Cytogenetic location: 17q11.2 Genomic coordinates (GRCh38) : 17:28,371,694-28,404,049 (from NCBI)
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned a partial cDNA encoding SARM, which they designated KIAA0524. RT-PCR analysis revealed near ubiquitous expression, with highest levels in kidney, followed by pancreas, prostate, ovary, small intestine, heart, brain, placenta, lung, and liver. Expression in other tissues was low.
Mink et al. (2001) identified the partial KIAA0524 sequence as the human homolog of the Drosophila CG7915 gene, and by BAC analysis they obtained a full-length cDNA encoding SARM. The deduced 690-amino acid SARM protein contains a 65-amino acid sterile alpha (SAM) domain surrounded by short HEAT/armadillo repeat sequences. The 3-prime untranslated region of the SARM mRNA is almost 5 kb. Northern blot analysis revealed expression of 3 faint transcripts of 6.5, 7.5, and 5.8 kb. The 6.5-kb transcript was the most abundant and showed highest expression in liver and kidney and weaker expression in placenta. A 0.45-kb transcript, representing an antisense RNA from the 5-prime region of the SARM gene, was also present in kidney and liver. No open reading frame was observed within this RNA sequence. In brain, only the 0.45-kb antisense RNA was detected at high abundance in the cerebellum and occipital pole and at lower levels in other brain regions. The antisense RNA was also detected at high levels in all cancer cell lines tested, irrespective of the tissue origin or metastatic potential. The protein-encoding SARM transcript was not expressed except in 1 prostate carcinoma cell line.
Carty et al. (2006) found that expression of TRIF (TICAM1; 607601) in macrophages led to activation of NFKB (see 164011) and IRF3 (603734), whereas expression of SARM had little or no effect. Increased SARM expression inhibited production of CCL5 (187011) and IRF7 (605047) after TLR3 (603029) or TLR4 (603030) activation, but not after TLR9 (605474) activation, indicating that SARM blocked TRIF-dependent, but not MYD88 (602170)-dependent, gene expression. Immunoprecipitation and yeast 2-hybrid analysis showed that SARM and TRIF interacted, and mutation analysis revealed that inhibition of TRIF by SARM required the sterile alpha motif and TIR domains of SARM. RNA-mediated interference of SARM blocked its ability to inhibit TRIF. Carty et al. (2006) concluded that, unlike the activating functions of other TIR adaptors, SARM is a negative regulator of TLR signaling.
Osterloh et al. (2012) showed that loss of Drosophila Toll receptor adaptor dSarm cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1-null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Osterloh et al. (2012) concluded that their results provided direct evidence that axons actively promote their own destruction after injury and identified dSarm/Sarm1 as a member of an ancient axon death signaling pathway.
Gerdts et al. (2015) reported that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD+) following axonemal injury. The authors used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD+, whereas SARM1-induced axon destruction could be counteracted by increased NAD+ synthesis. Gerdts et al. (2015) concluded that SARM1-induced depletion of NAD+ may explain the potent axon protection in Wallerian degeneration slow (wld-s) mutant mice (see 608700).
Zhu et al. (2019) found that knockdown of Sarm1 in mouse CAD5 neuronal cells significantly upregulated expression of the proapoptotic protein Xaf1 (606717).
Mink et al. (2001) determined that the mouse and human SARM genes contain 9 exons and span more than 24 kb. The SARM gene lies less than 1.8 kb centromeric to the vitronectin gene (VTN; 193190) in both the human and mouse genome, and the promoter regions of the 2 genes overlap. The mouse Ek1 gene lies within intron 1 of the mouse Sarm gene in the opposite orientation, but EK1 was not detected within human intron 1. In addition to numerous ubiquitous transcription factor-binding sequences, Mink et al. (2001) identified liver-specific transcriptional elements and kidney-specific transcriptional elements within the SARM promoter region.
Crystal Structure
Horsefield et al. (2019) showed that the Toll/interleukin-1 receptor (TIR) domain of SARM1 features self-association-dependent NAD+ cleavage activity associated with cell death signaling, and also showed that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ complexes of SARM1 and plant nucleotide-binding leucine-rich repeat (NLR) RUN1 TIR domains, respectively, revealed a conserved substrate binding site.
By radiation hybrid analysis, Nagase et al. (1998) mapped the SARM1 gene to chromosome 17. By genomic sequence analysis, Mink et al. (2001) mapped the SARM1 gene to chromosome 17q11.
Using quantitative RT-PCR and Western blot analyses, Zhu et al. (2019) showed that Sarm1 expression was significantly reduced in brains of prion-infected mice. Sarm1 -/- mice exhibited accelerated prion progression with no alteration in prion-induced neuroinflammation. RNA sequencing analysis demonstrated that Sarm1 deficiency selectively upregulated expression of Xaf1, which in turn enhanced neuronal apoptosis in prion-infected Sarm1 -/- mice.
Carty, M., Goodbody, R., Schroder, M., Stack, J., Moynagh, P. N., Bowie, A. G. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature Immun. 7: 1074-1081, 2006. [PubMed: 16964262] [Full Text: https://doi.org/10.1038/ni1382]
Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A., Milbrandt, J. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science 348: 453-457, 2015. [PubMed: 25908823] [Full Text: https://doi.org/10.1126/science.1258366]
Horsefield, S., Burdett, H., Zhang, X., Manik, M. K., Shi, Y., Chen, J., Qi, T., Gilley, J., Lai, J.-S., Rank, M. X., Casey, L. W., Gu, W., and 15 others. NAD+ cleavage activity by animal and plant TIR domains in cell death pathways. Science 365: 793-799, 2019. [PubMed: 31439792] [Full Text: https://doi.org/10.1126/science.aax1911]
Mink, M., Fogelgren, B., Olszewski, K., Maroy, P., Csiszar, K. A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/beta-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans. Genomics 74: 234-244, 2001. [PubMed: 11386760] [Full Text: https://doi.org/10.1006/geno.2001.6548]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Osterloh, J. M., Yang, J., Rooney, T. M., Fox, A. N., Adalbert, R., Powell, E. H., Sheehan, A. E., Avery, M. A., Hackett, R., Logan, M. A., MacDonald, J. M., Ziegenfuss, J. S., and 10 others. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337: 481-484, 2012. [PubMed: 22678360] [Full Text: https://doi.org/10.1126/science.1223899]
Zhu, C., Li, B., Frontzek, K., Liu, Y., Aguzzi, A. SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease. J. Exp. Med. 216: 743-756, 2019. [PubMed: 30842236] [Full Text: https://doi.org/10.1084/jem.20171885]