Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

SARM1 (Sterile Alpha and TIR Motif-Containing Protein 1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101818

Synonyms

Historical Background

Human sterile alpha and TIR motif-containing protein 1 (SARM1) gene was first cloned and described located at chromosome 17q11 by Mink et al. in 2001. It encodes a protein with domains of sterile alpha motif (SAM) and Armadillo motif (ARM) thus naming SARM (Mink et al. 2001). Later, a Toll/interleukin-1 receptor (TIR) domain was annotated in the C-terminal region of SARM; therefore it was renamed as SARM1 (O’Neill et al. 2003; Mink and Csiszar 2005). TIR domain is present in Toll-like receptors (TLRs), cytokine receptors, and cytoplasm adaptors that mediate innate immune responses to against microbiota infection. There are 10 TLRs in human and 13 TLRs in mice. Those TLRs recognize different components of pathogens and trigger signaling through TIR-TIR domain interactions with distinct TLR adaptors (O’Neill and Bowie 2007). Currently, TLR adaptors have five members including myeloid differentiation primary response gene 88 (MYD88), MYD88 adaptor-like (MAL), TIR domain-containing adaptor-inducing interferon (TRIF), TRIF-related adaptor molecule (TRAM), and SARM1. Among them, SARM1 is the most evolutionarily conserved TLR adaptor; its orthologs are present in various species from worms (C. elegans) to human (Mink et al. 2001; Yuan et al. 2010). As the Sarm1 knockout mice and the specific antibody were generated, the properties and biological function of SARM1 have been investigated in the immune and nervous systems.

Properties of SARM1

SARM1 Protein Features

SARM1 is a 724-amino-acid protein and contains a short mitochondria target peptide at the N-terminal end, followed by a regulatory domain, two SAM domains, and a C-terminal TIR domain (Fig. 1) (Mink et al. 2001; Panneerselvam et al. 2012; Gerdts et al. 2013). The SAM domains of SARM1 mediate the homomultimerization of SARM1 proteins, and SARM1 TIR domain is required to trigger the downstream signaling (Chuang and Bargmann 2005; Carty et al. 2006; Gerdts et al. 2013). The N-terminal regulatory domain of SARM1 has been suggested to intramolecularly interact with the SAM and/or TIR domains and thus inhibit the activity of SARM1 (Chuang and Bargmann 2005; Gerdts et al. 2013). Increase of intracellular calcium concentration likely changes the conformation of SARM1 and releases it from autoinhibition (Chuang and Bargmann 2005), although further confirmation is required. For the N-terminal first 27-amino-acid residues, it targets SARM1 to the outer membrane of mitochondria under the overexpression condition (Kim et al. 2007; Panneerselvam et al. 2012).
SARM1 (Sterile Alpha and TIR Motif-Containing Protein 1), Fig. 1

Protein domains and functions of SARM1. SAM, sterile alpha motif. TIR, Toll/interleukin-1 receptor

Expression Pattern of Sarm1

The expression pattern of Sarm1 was examined at both mRNA and protein levels (Kim et al. 2007; Chen et al. 2011). These studies revealed that SARM1 is profoundly expressed in mouse brain but not in the immune or other tissues. The SARM1 levels are highest from embryonic day 18 to postnatal day 7 and are reduced by 60% in adult. Furthermore, SARM1 is specifically present in neurons, including both excitatory and inhibitory neurons, but not microglial cells (Chen et al. 2011; Lin et al. 2014b). In neurons, SARM1 proteins are widely distributed in the soma, axon, dendrite, and dendritic spine (Chuang and Bargmann 2005; Kim et al. 2007; Chen et al. 2011). The data of immunostaining using a specific SARM1 antibody and knockin strategy tagging GFP to endogenous SARM1 clearly showed that SARM1 proteins are majorly cytoplasmic with only very small portion associated with the mitochondria (Kim et al. 2007; Chen et al. 2011; Osterloh et al. 2012). However, overexpressed SARM1 proteins predominantly associate with the outer mitochondrial membrane and trigger cell death (Kim et al. 2007; Panneerselvam et al. 2012). The reason of this distinct subcellular localization of endogenous and exogenous Sarm1 is currently unknown. Perhaps an unknown mechanism modulates Sarm1 localization, particularly prevention from mitochondria association, to avoid cell death.

Physiological Roles of SARM1

In the past decade, accumulating studies have shown that SARM1 plays multiple roles in defense of pathogen infection and brain development. It also mediates neuronal degeneration processes, such as Wallerian degeneration and ALS.

Innate Immune Response

The involvement of SARM1 in host defense is controversial. In C. elegans, TIR-1, SARM1 ortholog, is required for induction of immune response via P38 MAPK cascades (Fig. 2a) (Couillault et al. 2004; Liberati et al. 2004). On the other hand, human SARM1 negatively regulates MYD88- and TRIF-dependent TLRs signaling (Fig. 2b) (Carty et al. 2006; Peng et al. 2010). Furthermore, macrophages from SARM1 knockout mice show normal response to TLR ligands, such as polyinosinic:polycytidylic acid (poly(I:C)) and LPS (Kim et al. 2007). These results suggest that the evolutionarily conserved SARM1 has diverse host defense effect in different species.
SARM1 (Sterile Alpha and TIR Motif-Containing Protein 1), Fig. 2

SARM1 involves in host defense systems.(a) TIR-1, a SARM1 ortholog, acts through P38 MAPK cascades to trigger immune response after pathogen infection in C. elegans. (b) Human SARM1 inhibits both MYD88- and TRIF-dependent TLR3/4 signaling. TLR3 ligands, double-strand RNA or poly(I:C), activates TLR3 signaling through TRIF and the downstream factors such as TBK1, TRAF6, and PIPK1 to induce cytokine expression or apoptosis. LPS induces TLR4 signaling to trigger proinflammatory and anti-inflammatory cytokine expression via MYD88 and TRIF in plasma membrane or endosome, respectively. SARM1 inhibits both MYD88- and TRIF-dependent signaling

Neuronal Development

Given that SARM1 is abundantly expressed in neurons during development, several studies have investigated the function of SARM1 in neuronal morphogenesis. The role of SARM1 in neurons was first examined in C. elegans. TIR-1 is present at the postsynaptic synapse and acts downstream of CaMKII to regulate asymmetric expression of the odorant receptor in olfactory neurons via the ASK1-MAPK signaling during embryogenesis (Fig. 3a) (Chuang and Bargmann 2005). In Drosophila, transcription factor FoxO is controlled by Toll-6, a TLR in fly, and dSARM/SARM1 to promote microtubule dynamic and NMJ growth through suppressing Pavarotti/MKLP1 expression (Fig. 3b). Toll-6 overexpression increases the JNK activity and thus activates FoxO (McLaughlin et al. 2016).
SARM1 (Sterile Alpha and TIR Motif-Containing Protein 1), Fig. 3

SARM1 regulates neuronal development in distinct species. (a) TIR-1-MAPK signaling regulates asymmetric odorant receptor expression that subsequently determines the neuronal cell fate in C. elegans. Calcium and CaMKII act upstream of this process. (b) Toll-6, one of Drosophila TLRs, regulates FoxO translocation into the nucleus to suppress Pav-KLP expression. It consequently increases microtubule dynamic, promotes NMJ growth, and enhances presynaptic plasticity. The SARM1-JNK signaling acts downstream of Toll-6 and upstream of FoxO. (c) SARM1 receives signal from syndecan-2 or other factor and acts through the ASK1-MKK4/7-JNK cascade to increase microtubule stability and regulate dendritic arboration in mammalian

Using cultured hippocampal neurons, it has been shown that SARM1 receives signals from synaptic syndecan-2 and acts through the ASK1-MEK4/7-JNK pathway to control neuronal morphogenesis (Fig. 3c) (Chen et al. 2011). Given that SARM1 expression is earlier than syndecan-2, SARM1 likely receives signal(s) from other factor(s) and modulates neuronal development. Echoing the in vitro studies, SARM1 knockdown mice have smaller brain, less complex dendritic arbor, and aberrant spine density that result in impaired synaptic transduction (Chen et al. 2011; Lin et al. 2014a). These brain developmental defects also reflect in abnormal behaviors of the animals. SARM1 knockdown mice show deficits in associative memory, cognitive flexibility, and social interactions (Lin et al. 2014a; Lin and Hsueh 2014). Taken together, SARM1 regulates neural development in many different aspects, which are important for building up a functional brain with proper neuronal connections.

Axonal Degeneration and Cell Death

In addition to neural development, SARM1 also involves in controlling cell death and axonal degeneration. First of all, using SARM1 knockout mice, it has been demonstrated that loss of SARM1 in neurons prevents cell death under oxygen and glucose deprivation stress (Kim et al. 2007). It suggests that a destruction signaling is mediated by SARM1.

Secondarily, SARM1 is critical for Wallerian degeneration, a form of programmed self-destruction process that promotes axon breakdown in neurodegenerative diseases and axonal injury (Coleman and Freeman 2010; Conforti et al. 2014). A large-scale screening of mutant flies resistant to axon degeneration after axotomy identified SARM1 as the key mediator to trigger axon degeneration (Osterloh et al. 2012). In both flies and mice, loss of Sarm1 effectively suppresses Wallerian degeneration for weeks after axotomy, indicating that pro-degenerative signaling controlled by SARM1 is highly conserved in different species (Osterloh et al. 2012).

Recent works have revealed the upstream and downstream partners of SARM1 in injury-induced axon degeneration. Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an axonal protector counteracting the function of SARM1 in axon degeneration. NMNAT2 is required for converting nicotinamide mononucleotide (NMN) into nicotinamide adenine mononucleotide (NAD). Quickly degradation of NMNAT2 after axotomy results in the accumulation of NMN to trigger SARM1-dependent axon degeneration (Fig. 4) (Loreto et al. 2015). However, the mechanism underlying SARM1 activation by NMN is remained unclear. For the downstream signaling, a systematic screen of MAPK family study showed that SARM1 acts through the MEK4/7-JNK cascade to result in ATP depletion before physical breakdown of damaged axons (Yang et al. 2015).
SARM1 (Sterile Alpha and TIR Motif-Containing Protein 1), Fig. 4

SARM1 mediates axonal degeneration. Axonal injury induced by physical or chemical damage triggers SARM1 activation via loss of NMNAT2 or other unknown factor subsequently activates the MKK-JNK signaling and then causes cytoskeleton breakdown

In addition to Wallerian degeneration, Sarm1 knockout also attenuates axon degeneration after traumatic brain injury (McLaughlin et al. 2016). Moreover, loss of Sarm1 prevents motor neuron degeneration in an amyotrophic lateral sclerosis (ALS) disease model of C. elegans (Veriepe et al. 2015). These very recent studies support a role of SARM1 in neurodegenerative disorders.

Summary

Within a couple years, the function of SARM1 is largely explored in fields of innate immunity, neuronal development, and axonal degeneration. As a protein contained three protein-protein interaction domains (ARM, SAM, and TIR), SARM1 is expected to serve as an adaptor and involves in several signaling pathways. Being the identified fifth TLR adaptor, SARM1 acts very differently from the others, either cannot induce cytokine expression or activate TLR signaling. With the predominantly expression in the neuron and brain, the function of SARM1 in neuron has drawn more researchers’ attentions than before. Despite the argument in host defense system, SARM1 is required for neuronal morphogenesis and neuronal fate specification during development. On the other hand, SARM1 activates the death signal in the injured distal axons and leads to axonal destruction. Thus far, it is unclear how SARM1 can carry out these two distinct functions in neurons by using similar MAPK signaling pathway. It has been suggested that the conformational change of SARM1 modulates SARM1 function. Since the N-terminal regulatory domain of SARM1 modulates SARM1 signaling, it would be important to identify the interacting and/or the modification proteins of this region during neuronal development and axon injury.

See Also

References

  1. Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006;7:1074–81. doi:10.1038/ni1382.PubMedCrossRefGoogle Scholar
  2. Chen CY, Lin CW, Chang CY, Jiang ST, Hsueh YP. Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J Cell Biol. 2011;193:769–84. doi:10.1083/jcb.201008050.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Chuang CF, Bargmann CI. A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev. 2005;19:270–81. doi:10.1101/gad.1276505.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Coleman MP, Freeman MR. Wallerian degeneration, wld(s), and nmnat. Annu Rev Neurosci. 2010;33:245–67. doi:10.1146/annurev-neuro-060909-153248.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Conforti L, Gilley J, Coleman MP. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci. 2014;15:394–409. doi:10.1038/nrn3680.PubMedCrossRefGoogle Scholar
  6. Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, et al. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat Immunol. 2004;5:488–94. doi:10.1038/ni1060.PubMedCrossRefGoogle Scholar
  7. Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013;33:13569–80. doi:10.1523/JNEUROSCI.1197-13.2013.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C, et al. MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med. 2007;204:2063–74. doi:10.1084/jem.20070868.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Liberati NT, Fitzgerald KA, Kim DH, Feinbaum R, Golenbock DT, Ausubel FM. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci U S A. 2004;101:6593–8. doi:10.1073/pnas.0308625101.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Lin CW, Hsueh YP. Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice. Brain Behav Immun. 2014;37:142–51. doi:10.1016/j.bbi.2013.12.002.PubMedCrossRefGoogle Scholar
  11. Lin CW, Chen CY, Cheng SJ, Hu HT, Hsueh YP. Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator. Front Cell Neurosci. 2014a;8:87. doi:10.3389/fncel.2014.00087.PubMedPubMedCentralGoogle Scholar
  12. Lin CW, Liu HY, Chen CY, Hsueh YP. Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. Innate Immun. 2014b;20:161–72. doi:10.1177/1753425913485877.PubMedCrossRefGoogle Scholar
  13. Loreto A, Di Stefano M, Gering M, Conforti L. Wallerian degeneration is executed by an NMN-SARM1-dependent late Ca(2+) influx but only modestly influenced by mitochondria. Cell Rep. 2015;13:2539–52. doi:10.1016/j.celrep.2015.11.032.PubMedCrossRefGoogle Scholar
  14. McLaughlin CN, Nechipurenko IV, Liu N, Broihier HT. A Toll receptor-FoxO pathway represses Pavarotti/MKLP1 to promote microtubule dynamics in motoneurons. J Cell Biol. 2016;214:459–74. doi:10.1083/jcb.201601014.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Mink M, Csiszar K. SARM1: a candidate gene in the onset of hereditary infectious/inflammatory diseases. Clin Immunol. 2005;115:333–4. doi:S1521-6616(05)00069-0.Google Scholar
  16. 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. 2001;74:234–44. doi:10.1006/geno.2001.6548.PubMedCrossRefGoogle Scholar
  17. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64. doi:10.1038/nri2079.PubMedCrossRefGoogle Scholar
  18. O’Neill LA, Fitzgerald KA, Bowie AG. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol. 2003;24:286–90. doi:S1471490603001157.Google Scholar
  19. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, et al. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012;337:481–4. doi:10.1126/science.1223899.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Panneerselvam P, Singh LP, Ho B, Chen J, Ding JL. Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of the critical region and residues in the signal sequence. Biochem J. 2012;442:263–71. doi:10.1042/BJ20111653.PubMedCrossRefGoogle Scholar
  21. Peng J, Yuan Q, Lin B, Panneerselvam P, Wang X, Luan XL, et al. SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. Eur J Immunol. 2010;40:1738–47. doi:10.1002/eji.200940034.PubMedCrossRefGoogle Scholar
  22. Veriepe J, Fossouo L, Parker JA. Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat Commun. 2015;6:7319. doi:10.1038/ncomms8319.PubMedCrossRefGoogle Scholar
  23. Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, et al. Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell. 2015;160:161–76. doi:10.1016/j.cell.2014.11.053.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Yuan S, Wu K, Yang M, Xu L, Huang L, Liu H, et al. Amphioxus SARM involved in neural development may function as a suppressor of TLR signaling. J Immunol. 2010;184:6874–81. doi:10.4049/jimmunol.0903675.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Molecular BiologyTaipeiTaiwan