SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons

Mukherjee, Piyali; Winkler, Clayton W.; Taylor, Katherine; Woods, Tyson A.; Nair, Vinod; Khan, Burhan A.; Peterson, Karin E.

doi:10.4049/jimmunol.1500953

Cited by 51 publications

(35 citation statements)

References 36 publications

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“…Sterile alpha and TIR domain-containing 1 (SARM1) is a member of the Toll/ILR (TIR) domain-containing adaptor protein family and was recently identified as a mediator of axonal degeneration and neurodegeneration (33)(34)(35). To test the role of SARM1 as an adaptor protein in HERV-K RNA-triggered neuronal cell death, neurons from wild-type and Sarm1-deficient mice were incubated with HERV-K oligoribonucleotide.…”

Section: Herv-k Rna Causes Neuronal Injury Via Tlr Signaling In Vitromentioning

confidence: 99%

“…It has been previously identified as a regulator of neurodegeneration in Drosophila and mice, indicating SARM1 as a member of an ancient neuronal death signaling pathway (33). Virus-induced RIG-1/MAVS signaling as well as TLR7/TLR9 signaling cause mitochondrial accumulation of SARM in neurons (35,51), which triggers intrinsic apoptosis by generating reactive oxygen species and depolarizing the mitochondrial potential (52).…”

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confidence: 99%

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Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Dembny

Newman

Singh

et al. 2019

Preprint

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AbstractAlthough human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer’s disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

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Section: Herv-k Rna Causes Neuronal Injury Via Tlr Signaling In Vitromentioning

confidence: 99%

mentioning

confidence: 99%

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Dembny

Newman

Singh

et al. 2019

Preprint

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“…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 glucose deprivation, and viral infection (7)(8)(9)(10). Activated SARM1 can induce cell death independent of other known programmed cell death programs in a pathway termed sarmoptosis.…”

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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.

119

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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“…27 However, neurons have been reported to express all endosomally located TLRs (TLR3, TLR7, TLR8 and TLR9), which may be implicated in mechanisms of cell death but through ill-characterized mechanisms. 28 Toll-like receptor 9 is a canonical receptor that engages the innate immune response mediated by pathogenic DNA released from microbes and also from necrotic cells, where cell-derived DNA will act as major alarmins. TLR9 signaling can have contrasting effects: mediating either protective or pro-apoptotic activities.…”

Section: Discussionmentioning

confidence: 99%

CD93 is a cell surface lectin receptor involved in the control of the inflammatory response stimulated by exogenous DNA

Nativel

Ramin‐Mangata

Mevizou³

et al. 2019

Immunology

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Summary Bacterial DNA contains CpG oligonucleotide (ODN) motifs to trigger innate immune responses through the endosomal receptor Toll‐like receptor 9 (TLR9). One of the cell surface receptors to capture and deliver microbial DNA to intracellular TLR9 is the C‐type lectin molecule DEC‐205 through its N‐terminal C‐type lectin‐like domain (CTLD). CD93 is a cell surface protein and member of the lectin group XIV with a CTLD. We hypothesized that CD93 could interact with CpG motifs, and possibly serve as a novel receptor to deliver bacterial DNA to endosomal TLR9. Using ELISA and tryptophan fluorescence binding studies we observed that the soluble histidine‐tagged CD93‐CTLD was specifically binding to CpG ODN and bacterial DNA. Moreover, we found that CpG ODN could bind to CD93‐expressing IMR32 neuroblastoma cells and induced more robust interleukin‐6 secretion when compared with mock‐transfected IMR32 control cells. Our data argue for a possible contribution of CD93 to control cell responsiveness to bacterial DNA in a manner reminiscent of DEC‐205. We postulate that CD93 may act as a receptor at plasma membrane for DNA or CpG ODN and to grant delivery to endosomal TLR9.

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SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons

Cited by 51 publications

References 36 publications

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

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

CD93 is a cell surface lectin receptor involved in the control of the inflammatory response stimulated by exogenous DNA

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SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons

Cited by 51 publications

References 36 publications

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

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

CD93 is a cell surface lectin receptor involved in the control of the inflammatory response stimulated by exogenous DNA

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