Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of the critical region and residues in the signal sequence

Panneerselvam, Porkodi; Singh, Laishram Pradeepkumar; Ho, Bow; Chen, Jianzhu; Ding, Jeak Ling

doi:10.1042/bj20111653

Cited by 72 publications

(66 citation statements)

References 42 publications

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“…3 A, B). In contrast, SARM lacking the mitochondria-targeting residues 2-27 (SARM⌬N27) reported by Panneerselvam et al (2012) is diffusely localized in axons (Fig. 3C), confirming the importance of this region for mitochondrial targeting of SARM in neurons.…”

Section: Sarm Peripherally Associates With Neuronal Mitochondriamentioning

confidence: 76%

“…Two groups reported that SARM mediates oxygen/glucose-deprivationinduced neuronal death (Kim et al, 2007;Mukherjee et al, 2013). While SARM was shown to mediate T-cell death via an apoptotic pathway (Panneerselvam et al, 2013), the Caenohabditis elegans homolog of SARM, Tir-1, was found to be required for nonapoptotic programmed death of the linker cell during development …”

Section: Sam-tir Fragment Elicits Axon Degeneration and Nonapoptotic mentioning

confidence: 99%

“…Human SARM1 is a 724 aa protein with two clearly defined conserved domains identified by the Pfam sequence analysis tool (Finn et al, 2010): a pair of tandem SAM domains, which commonly mediate intramolecular and intermolecular interactions (Kim and Bowie, 2003;Qiao and Bowie, 2005); and, a TIR domain, which in other TIR-containing proteins can homodimerize and interact with TIR domains from other molecules (O'Neill and Bowie, 2007). The N terminus of SARM contains HEAT/Armadillo repeat domains (Mink et al, 2001), which commonly mediate protein binding, as well as an N-terminal mitochondrial targeting sequence (residues 1-27; Panneerselvam et al, 2012); however, neuronal studies concerning SARM localization to mitochondria are not in agreement (Kim et al, 2007;Chen et al, 2011;Osterloh et al, 2012).…”

Section: Sarm Promotes Axon Degeneration In Parallel With a Somaderivmentioning

confidence: 99%

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Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

et al. 2013

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Axon degeneration is an evolutionarily conserved pathway that eliminates damaged or unneeded axons. Manipulation of this poorly understood pathway may allow treatment of a wide range of neurological disorders. In an RNAi-based screen performed in cultured mouse DRG neurons, we observed strong suppression of injury-induced axon degeneration upon knockdown of Sarm1 [SARM (sterile ␣-motif-containing and armadillo-motif containing protein)]. We find that a SARM-dependent degeneration program is engaged by disparate neuronal insults: SARM ablation blocks axon degeneration induced by axotomy or vincristine treatment, while SARM acts in parallel with a soma-derived caspase-dependent pathway following trophic withdrawal. SARM is a multidomain protein that associates with neuronal mitochondria. Deletion of the N-terminal mitochondrial localization sequence disrupts SARM mitochondrial localization in neurons but does not alter its ability to promote axon degeneration. In contrast, mutation of either the SAM (sterile ␣ motif) or TIR (Toll-interleukin-1 receptor) domains abolishes the ability of SARM to promote axonal degeneration, while a SARM mutant containing only these domains elicits axon degeneration and nonapoptotic neuronal death even in the absence of injury. Protein-protein interaction studies demonstrate that the SAM domains are necessary and sufficient to mediate SARM-SARM binding. SARM mutants lacking a TIR domain bind full-length SARM and exhibit strong dominant-negative activity. These results indicate that SARM plays an integral role in the dismantling of injured axons and support a model in which SAM-mediated multimerization is necessary for TIR-dependent engagement of a downstream destruction pathway. These findings suggest that inhibitors of SAM and TIR interactions represent therapeutic candidates for blocking pathological axon loss and neuronal cell death.

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Section: Sarm Peripherally Associates With Neuronal Mitochondriamentioning

confidence: 76%

Section: Sam-tir Fragment Elicits Axon Degeneration and Nonapoptotic mentioning

confidence: 99%

Section: Sarm Promotes Axon Degeneration In Parallel With a Somaderivmentioning

confidence: 99%

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Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

et al. 2013

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“…To discriminate between these two possibilities, we investigated how the K597E mutation impacts the function of the constitutively active SAM-TIR fragment of SARM1. This fragment lacks the autoinhibitory N terminus, and its expression triggers spontaneous neuronal cell death (3,27) (Fig. 4A); however, like injuryinduced axon degeneration, its effects can be suppressed by the NAD + precursor nicotinamide riboside (NR) (4).…”

Section: Functional Analysis Of Tir Motifs In Sarm1-dependent Axonmentioning

confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

125

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Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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“…SARM contributes to the initiation, elongation, and maintenance of dendritic arbors and influences axonal death and neuronal polarization (15)(16)(17). Recent studies have shown that SARM directly binds to mitochondria (18) and induces apoptosis in T cells (19). However, whether human SARM has an antiviral role has not yet been elucidated.…”

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confidence: 99%

Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection

Liu

Zang

Zhou

et al. 2014

J Virol

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Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children ELISA). SARM expression was reduced and TRIF expression was increased after infection with RSV. Resveratrol increased SARM expression and decreased TRIF expression after RSV infection. SARM knockdown in resveratrol-treated mice enhanced gamma interferon production, RSV-induced airway inflammation, and airway hyperresponsiveness (AHR). Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression. Resveratrol-mediated inhibition of the TRIF-dependent pathway may be dependent on SARM expression. IMPORTANCEOur study provides insights into the regulation of innate immunity in response to RSV infection. The results suggest that resveratrol-mediated alterations in SARM have therapeutic potential against RSV immunopathology caused by deregulation of the TLR-mediated immune response. Ultimately, improved insight into the complex interplay between TLR adaptor proteins and the occurrence of severe RSV infection might lead to novel therapeutic treatment strategies, such as TLR adjuvants.

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Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of the critical region and residues in the signal sequence

Cited by 72 publications

References 42 publications

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection

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Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of the critical region and residues in the signal sequence

Cited by 72 publications

References 42 publications

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation