Affinage

SARM1

NAD(+) hydrolase SARM1 · UniProt Q6SZW1

Length
724 aa
Mass
79.4 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SARM1 is an injury-activated NAD+-cleaving enzyme that functions as the central executioner of programmed axon self-destruction (Wallerian degeneration) and additionally serves as a regulator of innate immune signaling (PMID:30642945, PMID:16964262). The protein assembles into an autoinhibited homo-octameric ring built from SAM-domain 'lock and key' interfaces, with the catalytic TIR domains held isolated and inactive by NAD+ bound at an allosteric site in the N-terminal ARM domain and by multiple intramolecular ARM–TIR locks (PMID:31278906, PMID:33053563, PMID:33185189, PMID:33468661). Axon injury raises the NMN/NAD+ ratio; NMN competes with NAD+ at the ARM allosteric pocket, breaks the ARM–TIR lock, and triggers the conformational change that frees the TIR domains to dimerize and consume NAD+ catastrophically (PMID:32755591, PMID:33657413, PMID:36550129). The NADase activity, which resides in the TIR domain and depends on conserved catalytic residues, is essential for degeneration: forced TIR dimerization causes NAD+ loss and neuronal death, and NADase-dead or dominant-negative constructs protect axons in vitro and in vivo (PMID:27671644, PMID:30642945, PMID:32828421). Downstream, SARM1 NADase activity initiates an ordered collapse — ATP loss, mitochondrial depolarization, calcium influx, phosphatidylserine externalization, and membrane rupture (PMID:34779400, PMID:25009267). SARM1 acts genetically downstream of loss of the axon survival factor NMNAT2, and diverse insults including mitochondrial depolarization, TNF-driven noncanonical necroptosis (via MLKL-dependent NMNAT2/STMN2 loss), and the neurotoxin vacor converge on this NMN/NAD+-sensing switch (PMID:25818290, PMID:25009267, PMID:32609299, PMID:34870595). The pathway is pharmacologically tractable: NaMN is an endogenous allosteric inhibitor, and covalent ligands targeting ARM cysteine C311 block degeneration (PMID:34403688, PMID:35994671). Genetic deletion of Sarm1 rescues axonal, synaptic, and mitochondrial pathology in a CMT2A (Mfn2) model, defining a feedback loop between mitochondrial dysfunction and SARM1 activation (PMID:36287202). Separately, SARM1 negatively regulates TRIF-dependent TLR signaling and restrains the NLRP3 inflammasome to suppress IL-1β and pyroptosis through both NADase-dependent and NADase-independent mechanisms (PMID:16964262, PMID:31076360, PMID:38832024).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2006 High

    Established the first molecular function of SARM1, identifying it as a negative regulator that physically engages the TLR adaptor TRIF, defining a role outside the nervous system.

    Evidence Co-IP of SARM–TRIF and RNAi knockdown with cytokine reporters in human cells

    PMID:16964262

    Open questions at the time
    • Did not define the structural basis of TRIF binding
    • Did not address any neuronal function
  2. 2013 High

    Defined SARM1 as a pro-degenerative factor and mapped the SAM domains to oligomerization and the TIR domain to engagement of a destruction pathway, framing the modular logic of the protein.

    Evidence RNAi screen in DRG neurons with domain-deletion/point mutants, co-IP, genetic KO, and dominant-negative overexpression

    PMID:23946415

    Open questions at the time
    • Enzymatic identity of the TIR domain not yet known
    • Activating signal upstream not defined
  3. 2014 High

    Placed SARM1 downstream of ROS and mitochondrial depolarization in a distinct neuronal death program, ordering it within the degeneration cascade.

    Evidence CCCP depolarization with Sarm1-null neurons, ROS/ATP/calcium readouts

    PMID:25009267

    Open questions at the time
    • Molecular sensor linking depolarization to SARM1 not identified
    • Catalytic mechanism still unknown at this stage
  4. 2015 High

    Established genetic epistasis showing SARM1 acts downstream of NMNAT2 loss, linking axon survival-factor turnover to a SARM1-dependent destruction pathway.

    Evidence Double Sarm1/Nmnat2 knockout mice with NAMPT inhibition and metabolite measurement

    PMID:25818290

    Open questions at the time
    • Did not establish NMN as the direct activating ligand
    • Mechanism connecting NMNAT2 loss to SARM1 activity not resolved
  5. 2016 High

    Identified the TIR domain as the source of NAD+-consuming activity unique among TIR adaptors and conserved to C. elegans, recasting SARM1 as an enzyme rather than a scaffold.

    Evidence Forced TIR dimerization, in-cell NAD+ measurement, mutagenesis, N-terminus–TIR co-IP, C. elegans genetics

    PMID:27671644

    Open questions at the time
    • Did not directly measure purified-enzyme NADase kinetics
    • Structural basis of autoinhibition not yet solved
  6. 2019 High

    Directly demonstrated injury-activated intrinsic NADase activity is essential for degeneration and that blocking it is axon-protective in vivo, validating SARM1 as a therapeutic target.

    Evidence In vitro NADase assay, AAV delivery of dominant-negative constructs, nerve transection, KO comparison

    PMID:30642945

    Open questions at the time
    • Did not resolve the allosteric activation mechanism
    • Octameric architecture not yet defined
  7. 2019 High

    Solved the octameric ring architecture and mapped SAM–SAM interfaces, providing the structural unit of SARM1 assembly.

    Evidence Crystal structure of SAM1-2, EM of full-length protein, SEC, mutagenesis, cell-death assay

    PMID:31278906

    Open questions at the time
    • Did not capture the autoinhibitory ARM–TIR contacts
    • Did not define the activating ligand
  8. 2020 High

    Converging cryo-EM studies established that NAD+ binding to the ARM domain enforces an autoinhibited octamer that locks TIR domains apart, with NMN acting as an endogenous activator that disrupts the ARM–TIR lock.

    Evidence Multiple cryo-EM structures of autoinhibited and active states, NADase assays, product-inhibition, and interface mutagenesis (Nature, Cell Reports, eLife)

    PMID:32755591 PMID:33053563 PMID:33185189

    Open questions at the time
    • Atomic-resolution NMN-bound activated catalytic site not fully resolved
    • Dynamics of TIR dimerization during catalysis incompletely defined
  9. 2020 High

    Identified cADPR as an in vivo product of SARM1 NAD+ cleavage and a quantitative biomarker, while showing it is not the effector of degeneration.

    Evidence Mass spectrometry, Sarm1 gene-dosage series, in vivo nerve injury, engineered cADPR-cleaving enzymes

    PMID:32087251

    Open questions at the time
    • The metabolic consequence driving degeneration (vs cADPR) not isolated here
    • Basal physiological role of constitutive activity unclear
  10. 2021 High

    Established the NMN/NAD+ ratio as the activating signal through competitive ARM-domain binding, unifying the metabolic trigger with the structural switch.

    Evidence Cryo-EM/crystallography of ARM–NMN, biophysical binding, NADase assays, mutagenesis, cellular degeneration; plus mapping of five autoinhibitory interfaces

    PMID:33468661 PMID:33657413

    Open questions at the time
    • In vivo dynamics of NMN/NAD+ sensing during injury not directly imaged
    • How multiple interfaces release sequentially not resolved
  11. 2021 High

    Resolved the temporal order of downstream destruction events at single-axon resolution, placing NADase activity at the apex of an ATP→mitochondrial→calcium→membrane cascade.

    Evidence Live imaging of single sensory axons with genetically encoded ATP/calcium/PS sensors and KO controls

    PMID:34779400

    Open questions at the time
    • Molecular link from NAD+ loss to calcium influx not pinned to specific channels
    • PS-externalization machinery not identified
  12. 2021 High

    Expanded the activator/inhibitor pharmacology by structurally defining the potent activator VMN and the endogenous inhibitor NaMN at the ARM allosteric pocket, plus pH and salt-bridge determinants of activation.

    Evidence Crystal structures of ARM–VMN and ARM–NaMN, NADase competition assays, mutagenesis (E689/R216 salt bridge), neuron protection

    PMID:34213829 PMID:34403688 PMID:34870595

    Open questions at the time
    • NaMN-based therapeutic window in vivo not established here
    • Physiological relevance of pH activation not defined
  13. 2022 High

    Identified druggable allosteric and catalytic sites (covalent C311 ligands, catalytic cysteines, zinc) enabling small-molecule inhibition of degeneration.

    Evidence Chemical proteomics with C311 mutagenesis and DRG degeneration assays; high-throughput NADase screen with C629/C635 mutagenesis

    PMID:32828421 PMID:35994671

    Open questions at the time
    • In vivo efficacy and selectivity of covalent inhibitors not fully established
    • Relationship between catalytic cysteines and the NAD+ catalytic mechanism not structurally resolved
  14. 2022 High

    Captured the activated, conformationally dynamic state by cryo-EM and native MS, showing ARM inward bending and transient BB-loop-mediated TIR dimers as the catalytic species.

    Evidence Activation-state-specific nanobody, cryo-EM of NMN/SARM1/Nb-C6, native MS and HDX-MS

    PMID:36550129

    Open questions at the time
    • High-resolution structure of the catalytically competent TIR dimer not solved
    • Whether the octamer disassembles or remains intact during catalysis debated
  15. 2022 High

    Showed SARM1 activation drives disease in a CMT2A mitochondrial-mutation model, with Sarm1 deletion rescuing both axonal and mitochondrial pathology, establishing a degenerative feedback loop.

    Evidence Sarm1-/- × Mfn2H361Y double-mutant rat model with NMJ histology, EM, and behavior

    PMID:36287202

    Open questions at the time
    • Did not define the molecular signal from mutant mitochondria to SARM1
    • Generalizability to other CMT subtypes not tested
  16. 2023 High

    Demonstrated that SARM1 NADase activity also drives non-degenerative developmental and immune phenotypes (Drosophila NMJ growth; C. elegans p38/PMK-1 innate immunity via stress-induced phase transition), distinguishing degenerative from physiological signaling.

    Evidence Graded-NADase transgenic Drosophila and C. elegans TIR-1 imaging/enzymology with infection assays

    PMID:35098926 PMID:35737728

    Open questions at the time
    • Whether mammalian SARM1 supports analogous developmental NADase signaling not shown
    • Effectors linking NADase output to p38/MAPK not defined
  17. 2023 High

    Resolved a NADase-independent arm of SARM1 function in axon regeneration via MAPK cascades, separating its scaffolding/signaling roles from its enzymatic destruction role.

    Evidence C. elegans tir-1 mutants and NADase-deficient SARM1 with NSY-1/ASK1 and DLK-1 epistasis, human SARM1 in worms

    PMID:37083456

    Open questions at the time
    • Mammalian regeneration role of SARM1 not fully mapped
    • Molecular partners coupling SARM1 to ASK1/DLK1 not identified
  18. 2024 Medium

    Dissected the dual NADase-dependent and -independent immune functions in human cells, showing TNF and IL-1β are controlled through distinct enzymatic and non-enzymatic routes.

    Evidence SARM1-KO human monocytes with NADase-inactive mutant, TLR4 stimulation, ELISA/RT-PCR, NLRP3 assay

    PMID:38832024

    Open questions at the time
    • Direct molecular targets of the NADase-independent suppression not identified
    • Single-lab finding in monocytes; in vivo relevance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same NMN/NAD+-sensing enzyme is wired to opposing outcomes — axon destruction, axon regeneration inhibition, developmental NMJ growth, and immune regulation — across cell types and subcellular pools remains unresolved.
  • Subcellular pools (mitochondrial vs cytosolic) directing distinct functions not fully mapped
  • The effectors translating NAD+ loss into calcium influx and membrane breakdown are unidentified
  • How non-enzymatic SARM1 signaling engages MAPK and immune pathways mechanistically is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0140299 molecular sensor activity 3 GO:0016787 hydrolase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
MYD88NLRX1PINK1TRAF6TRIFTRPV1ULK1UXT
Complex memberships
SARM1 homo-octamerSARM1–PINK1–TRAF6 mitochondrial complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SARM (SARM1) functions as a negative regulator of TRIF-dependent Toll-like receptor signaling; it physically associates with TRIF, and knockdown of endogenous SARM by RNAi enhances TRIF-dependent cytokine and chemokine induction, while SARM overexpression blocks gene induction downstream of TRIF but not MyD88. Co-immunoprecipitation (SARM–TRIF interaction), RNAi knockdown in human cells, reporter/cytokine assays Nature Immunology High 16964262
2013 SARM1 promotes injury-induced axon degeneration; both the SAM and TIR domains are required for this activity. SAM domains mediate SARM1 homo-oligomerization and are necessary and sufficient for SARM–SARM binding, while TIR domain engagement of a downstream destruction pathway is required for degeneration. A construct containing only SAM+TIR elicits degeneration even without injury, and SARM mutants lacking TIR act as dominant negatives. SARM1 associates with neuronal mitochondria, but deletion of the N-terminal mitochondrial localization sequence does not alter pro-degenerative function. RNAi screen in DRG neurons, domain-deletion and point-mutation analysis, protein–protein interaction (co-IP), live-cell imaging, genetic knockout, dominant-negative overexpression The Journal of Neuroscience High 23946415
2016 Dimerization of the SARM1 TIR domain promotes NAD+ consumption and neuronal destruction; this NADase activity is unique to SARM1 among TIR adaptors and is evolutionarily conserved (C. elegans TIR-1 TIR dimerization also causes NAD+ loss). A SARM1-specific 'SS loop' and canonical TIR motifs are required for NAD+ loss and axon degeneration. A residue in the BB loop is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1. A physical interaction between the autoinhibitory N-terminus and the TIR domain of SARM1 was identified, suggesting a direct intramolecular autoinhibitory mechanism. Forced TIR dimerization, in-cell NAD+ measurement, mutagenesis, co-immunoprecipitation (N-terminus–TIR interaction), C. elegans genetic analysis Proceedings of the National Academy of Sciences High 27671644
2019 SARM1 is an injury-activated NAD+ cleavage enzyme (NADase); its intrinsic NADase activity in the TIR domain is essential for its pro-degenerative function. Dominant-negative SARM1 constructs that block NADase activity potently protect axons from degeneration in vitro and in vivo when delivered by AAV. In vitro NADase assay, AAV-mediated gene delivery, nerve transection model, genetic knockout comparison The Journal of Experimental Medicine High 30642945
2019 SARM1 assembles into a homo-octameric ring; both full-length SARM1 and the isolated tandem SAM1-2 domains form octamers in solution and in crystal lattice. SAM–SAM ring interfaces are mediated by hydrophobic 'lock and key' grooves and electrostatic interactions between neighboring protomers. Mutation of critical SAM oligomerization interfaces reduces SARM1-dependent cell death. Crystal structure of SAM1-2 domains, electron microscopy of full-length SARM1, size-exclusion chromatography, mutagenesis, cell-death assay Journal of Molecular Biology High 31278906
2020 NAD+ is an allosteric ligand of the ARM domain of SARM1 that mediates self-inhibition; NAD+ binding to ARM facilitates inhibition of the TIR-domain NADase through the ARM–TIR domain interface. Cryo-EM structures of full-length SARM1 revealed the autoinhibited octameric state. Disruption of the NAD+-binding site or the ARM–TIR interaction causes constitutive SARM1 activation and axonal degeneration. Cryo-EM (full-length SARM1), in vitro NADase assay, mutagenesis, cellular axon-degeneration assay Nature High 33053563
2020 Cryo-EM structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) show that both states retain an octameric core; the autoinhibited state features a lock between the ARM domain and the TIR domain. Mutations breaking this ARM–TIR lock activate SARM1 and cannot be further activated by NMN. Active SARM1 is product-inhibited by nicotinamide (NAM). NMN acts as an endogenous activator by disrupting the ARM–TIR lock. Cryo-EM, in vitro NADase assay, mutagenesis, product-inhibition experiments Cell Reports High 32755591
2020 Cryo-EM maps of SARM1 at 2.9 and 2.7 Å show that the inactive homo-octamer is stabilized by NAD+ binding at an allosteric site away from the catalytic TIR sites, preventing premature dimerization of catalytic domains. Mutagenesis of this allosteric site causes constitutively active SARM1. NAD+ depletion is proposed to promote disassembly of the peripheral ring and formation of active NADase domain dimers. Cryo-EM, allosteric site mutagenesis, in vitro NADase assay eLife High 33185189
2021 SARM1 is activated by an increase in the NMN/NAD+ ratio: NMN and NAD+ compete for binding to the autoinhibitory ARM domain, and NMN binding induces a conformational change that activates SARM1 NADase. Structures of the ARM domain bound to NMN and of the unliganded octameric SARM1 complex were determined. Mutagenesis demonstrated that NMN binding to ARM is required for injury-induced SARM1 activation and axon destruction. Cryo-EM / X-ray crystallography of ARM–NMN complex, biophysical binding assays, in vitro NADase assay, mutagenesis, cellular axon-degeneration assay Neuron High 33657413
2021 Multiple intramolecular and intermolecular domain interfaces are required for SARM1 autoinhibition: ARM–SAM interfaces (intra- and intermolecular), an intermolecular ARM–ARM interface, and two ARM–TIR interfaces (one TIR contacting two distinct ARM domains). Cryo-EM reveals a compact autoinhibited octamer in which TIR domains are isolated. Point mutations in each of five distinct interfaces independently render SARM1 constitutively active. Cryo-EM of autoinhibited octamer, peptide-mapping/inhibition assay, mutagenesis, in-cell NAD+ measurement, axon-degeneration assay Proceedings of the National Academy of Sciences High 33468661
2015 SARM1 acts downstream of NMNAT2 loss in a linear or convergent pathway: axon degeneration induced specifically by NMNAT2 depletion requires SARM1, and SARM1 deficiency corrects both axon degeneration and restricted axon outgrowth in NMNAT2-deficient mice. NAMPT inhibition (reducing NMN) partially restores outgrowth of NMNAT2-deficient axons, implicating NMN accumulation upstream of SARM1. Genetic epistasis (double Sarm1/Nmnat2 knockout mice), pharmacological NAMPT inhibition, metabolite measurement Cell Reports High 25818290
2014 Mitochondrial depolarization triggers SARM1-dependent axon degeneration and neuronal cell death in sensory neurons; SARM1 acts downstream of ROS generation (ATP depletion, calcium influx, and ROS accumulation still occur in Sarm1-null neurons, yet death is blocked), defining a SARM1-dependent cell death program termed 'sarmoptosis'. Pharmacological mitochondrial depolarization (CCCP), Sarm1 genetic knockout, cell-death assays, ROS measurement, ATP measurement, calcium imaging The Journal of Neuroscience High 25009267
2013 SARM1 forms a complex with PINK1 and TRAF6 on depolarized mitochondria; SARM1 promotes TRAF6-mediated K63-chain ubiquitination of PINK1 at K433, stabilizing PINK1 on the outer mitochondrial membrane and facilitating parkin recruitment for mitophagy. Knockdown of SARM1 or TRAF6 abrogates PINK1 accumulation and parkin recruitment. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mitochondrial fractionation, fluorescence microscopy Molecular Biology of the Cell Medium 23885119
2012 Mitochondria-localized SARM promotes intrinsic apoptosis in T cells during immune activation via ROS generation, mitochondrial depolarization, suppression of Bcl-xL, and downregulation of ERK phosphorylation. The pro-apoptotic function is attributable to the C-terminal SAM and TIR domains. Bcl-xL overexpression and Bax/Bak double-knockout substantially reduce SARM-induced apoptosis. SARM knockdown/overexpression in T cells, in vivo influenza infection model, Bcl-2 family genetic rescue, caspase activation assay, ROS/mitochondrial potential measurements Cell Death and Differentiation Medium 23175186
2019 SARM suppresses the NLRP3 inflammasome directly, restraining caspase-1 activation and IL-1β secretion; pyroptosis-inducing NLRP3 stimulants cause SARM-dependent mitochondrial depolarization that distinguishes pyroptotic from hyperactivating stimuli. Sarm1-/- macrophages display increased IL-1β but reduced pyroptosis, and Sarm1-/- mice are protected from LPS-induced sepsis. Sarm1 genetic knockout macrophages and mice, caspase-1 activation assay, NLRP3 co-IP/functional assay, mitochondrial depolarization measurement, LPS sepsis model Immunity High 31076360
2020 TNF-α induces SARM1-dependent axon degeneration via a noncanonical necroptotic signaling mechanism in which MLKL causes loss of axon survival factors NMNAT2 and STMN2, thereby activating SARM1 NADase activity, leading to calcium influx and axon degeneration. MLKL does not directly trigger degeneration in axons; rather it acts upstream of SARM1 through NMNAT2/STMN2 loss. Genetic knockout (Sarm1, MLKL), siRNA knockdown, NAD+ measurement, calcium imaging, glaucoma neuroinflammation model The Journal of Cell Biology High 32609299
2020 cADPR is a product of SARM1-dependent NAD+ cleavage in neurons and nerves in vivo; SARM1 is a major source of cADPR in DRG neurons, sciatic nerve, and brain, and has basal enzymatic activity in healthy tissue. Post-injury cADPR levels increase dramatically in proportion to SARM1 gene dosage, validating cADPR as a SARM1 activity biomarker. Manipulation of cADPR levels does not alter axon degeneration time course, indicating cADPR is not a key effector of degeneration. Mass spectrometry measurement of cADPR, SARM1 genetic knockout/heterozygous dosage series, in vivo nerve injury, engineered cADPR-cleaving enzymes Experimental Neurology High 32087251
2021 Live imaging of single mouse sensory axons shows that SARM1 NADase activity initiates an ordered sequence of events: loss of cellular ATP → defects in mitochondrial movement and depolarization → calcium influx → phosphatidylserine externalization → loss of membrane permeability → catastrophic axon self-destruction. Live fluorescence imaging of single axons, genetically encoded sensors (ATP, calcium, PS), SARM1 knockout comparison eLife High 34779400
2021 A crystal structure of the Drosophila SARM1 regulatory (ARM) domain complexed with the potent activator VMN (vacor metabolite, an NMN analog) reveals the structural basis for activator binding. VMN is the most potent SARM1 activator known, and SARM1 deletion completely rescues neurons from vacor-induced degeneration in vitro and in vivo. X-ray crystallography of ARM–VMN complex, genetic Sarm1 knockout, in vitro neuron protection assay, in vivo mouse model eLife High 34870595
2021 Nicotinic acid mononucleotide (NaMN) is an allosteric SARM1 inhibitor that competes with NMN for binding to the SARM1 ARM domain allosteric pocket and promotes the open, autoinhibited ARM conformation. Co-crystal structure of NaMN with the ARM domain shows direct binding to the allosteric site, and NaMN-mediated SARM1 inhibition contributes to long-term axon protection. X-ray crystallography (ARM–NaMN complex), in vitro NADase competition assay, mutagenesis, neuronal axon protection assay Experimental Neurology High 34403688
2022 Tryptoline acrylamide compounds site-specifically and stereoselectively modify cysteine-311 (C311) in the non-catalytic ARM domain of SARM1, allosterically inhibiting NADase activity. C311A/C311S mutants are resistant to inhibition. These covalent inhibitors stereoselectively block vincristine- and vacor-induced neurite degeneration in primary DRG neurons. Chemical proteomics (activity-based protein profiling), site-directed mutagenesis, in vitro NADase assay, primary neuron degeneration assay Proceedings of the National Academy of Sciences High 35994671
2022 C. elegans TIR-1/SARM1 undergoes a phase transition (oligomerization into visible puncta) upon physiological stress, and this multimerization dramatically potentiates its NAD+ glycohydrolase activity in vitro. Genetic mutations blocking either multimerization or NADase activity prevent p38/PMK-1 immune pathway activation and increase susceptibility to bacterial infection, placing TIR-1 NADase activity downstream of oligomerization and upstream of p38 MAPK. Fluorescence imaging of TIR-1–GFP puncta, in vitro enzyme kinetics, C. elegans genetics (loss-of-function mutants, epistasis), p38 phosphorylation assay, infection survival assay eLife High 35098926
2022 ULK1 (autophagy kinase) physically interacts with SARM1 via SARM1 SAM domains, and this interaction increases upon neurite damage. ULK1 inhibition or Ulk1 knockdown attenuates SARM1 puncta accumulation in neurites and reduces neurite fragmentation. In vivo, axonal ULK1 activation and SARM1 accumulation are both reduced in Beclin1 autophagy hypomorph mice after SCI. Co-immunoprecipitation (in vitro and in vivo), domain-deletion analysis (SAM domains), ULK1 inhibitor and siRNA knockdown, immunofluorescence, spinal cord injury mouse model Proceedings of the National Academy of Sciences Medium 36375051
2022 In C. elegans and mammalian neurons, TIR-1/SARM1 cell-autonomously inhibits axon regeneration by activating the NSY-1/ASK1 MAPK cascade, independently of its NADase activity and degeneration-promoting function. Simultaneously, TIR-1 promotes axon degeneration on the other side of the injury via the DLK-1 MAPK cascade. Human SARM1 also inhibits axon regeneration cell-intrinsically. C. elegans tir-1 mutants (loss-of-function), NADase-deficient SARM1 variants, epistasis with NSY-1/ASK1 and DLK-1 pathway mutants, human SARM1 expression in C. elegans, axon regeneration imaging eLife High 37083456
2022 SARM1-dependent NAD+ hydrolysis is required for Drosophila neuromuscular junction (NMJ) development: NMJ overgrowth scales with the amount of SARM1 NADase activity, and degenerative and developmental SARM1 signaling use distinct upstream and downstream mechanisms despite sharing the NADase requirement. Transgenic Drosophila with graded NADase-activity SARM1 variants, NMJ morphometry, genetic epistasis PLoS Genetics Medium 35737728
2010 SARM inhibits MAPK activation (both TRIF- and MyD88-mediated, and basal) leading to suppression of AP-1, in addition to NF-κB and IRF3. RNAi knockdown of SARM elevates basal AP-1 activity. Truncated SARM changes subcellular localization, indicating that the N-terminal and SAM domains regulate SARM subcellular distribution and activity. Overexpression and RNAi knockdown, MAPK phosphorylation assay, AP-1 reporter assay, subcellular fractionation/localization European Journal of Immunology Medium 20306472
2015 The BB-loop residue G601 in the SARM TIR domain is essential for SARM's interaction with both MyD88 and TRIF; a G601A mutant loses the ability to suppress LPS-induced IL-8 and TNF-α. A short peptide derived from the BB-loop motif also interacts with MyD88 in vitro, demonstrating that the BB loop mediates SARM–adaptor TIR–TIR interactions. Recombinant TIR domain interaction assays (in vitro), site-directed mutagenesis (G601A), cytokine reporter assays in HEK293 cells Biochimica et Biophysica Acta Medium 26592460
2014 SARM is required for CCL5 production in macrophages across multiple pattern-recognition pathways (TLR and cytosolic RNA/DNA sensing). SARM acts at the level of the Ccl5 promoter, being critical for recruitment of transcription factors and RNA polymerase II, without affecting MAPK or NF-κB/IRF activation, mRNA stability, or splicing. Sarm1-/- macrophages, ELISA, chromatin immunoprecipitation (transcription factor and Pol II at Ccl5 promoter), RT-PCR, cytokine profiling Journal of Immunology Medium 24711619
2018 NLRX1 associates with SARM1 at the mitochondrial matrix in non-neuronal cells; in these cells, the apoptotic role of NLRX1 is fully dependent on SARM1, placing SARM1 downstream of NLRX1 in apoptosis regulation. Wallerian degeneration in primary neurons occurs in a SARM1-dependent but NLRX1-independent manner, indicating that different SARM1 subcellular pools mediate distinct functions. Co-immunoprecipitation (endogenous NLRX1–SARM1), mitochondrial fractionation, siRNA knockdown, Sarm1-/- neurons, cell-death assay Molecular and Cellular Biochemistry Medium 30191480
2013 UXT isoforms differentially regulate SARM-induced apoptosis: UXT V1 reduces caspase-8 activity (anti-apoptotic), while UXT V2 strongly increases caspase-8 and enhances SARM-induced apoptosis via the extrinsic pathway and mitochondrial depolarization. Both isoforms interact with SARM by yeast two-hybrid analysis. Yeast two-hybrid (UXT–SARM interaction), overexpression, caspase-8 activity assay, mitochondrial depolarization measurement FEBS Letters Low 24021647
2022 A nanobody (Nb-C6) specifically recognizes NMN-activated SARM1. Cryo-EM of the NMN/SARM1/Nb-C6 complex reveals an octameric structure in which ARM domains bend significantly inward and swing outward together with TIR domains upon activation. Nb-C6 binds the SAM domain of activated SARM1. Mass spectrometry indicates that activated SARM1 in solution is highly dynamic, with neighboring TIRs forming transient dimers via the BB-loop surface. Nanobody generation, cryo-EM of activated SARM1 complex, native mass spectrometry, hydrogen–deuterium exchange MS Nature Communications High 36550129
2021 Acidic pH (protonation of negative residues) activates SARM1 enzymatic activity even more efficiently than NMN. Mutagenesis revealed: E689Q in TIR constitutively activates SARM1 by disrupting a salt bridge with R216 in ARM that maintains autoinhibition; K597E inhibits activation; H685A eliminates catalytic activity. Distinct classes of chemical inhibitors act either by blocking activation (NAD, dHNN, disulfiram) or by inhibiting catalysis (nicotinamide, Tweens). In vitro NADase assay at varying pH, systematic site-directed mutagenesis, inhibitor classification The FEBS Journal Medium 34213829
2020 Cysteines 629 and 635 in the SARM1 TIR domain are critical for SARM1 catalysis; site-directed mutagenesis of these residues abolishes or reduces NADase activity. Zinc chloride inhibits SARM1 in a noncompetitive manner, suggesting an allosteric binding pocket on SARM1. High-throughput NADase screen, noncompetitive inhibition kinetics, site-directed mutagenesis (C629 and C635) Bioorganic & Medicinal Chemistry Medium 32828421
2022 In C. elegans, CaMKII/UNC-43 activates the conserved Sarm1/TIR-1–ASK1/NSY-1–p38 MAPK pathway to protect against axon degeneration caused by loss of mitochondria. Disruption of a trafficking complex (calsyntenin/CASY-1, Mint/LIN-10, kinesin) activates this CaMKII–Sarm1–MAPK neuroprotective pathway through L-type voltage-gated calcium channels. Unbiased genetic screen, C. elegans genetics (loss-of-function and epistasis), in vivo axon imaging eLife Medium 35285800
2023 TRPV1 interacts with SARM1 via TRPV1's N-terminal ankyrin repeat domain binding to the TIR-His583 domain of SARM1. This interaction, confirmed by co-IP, SPR, BRET, and NanoBiT, is required for TRPV1 to maintain hepatic stellate cell quiescence and prevent NF-κB-dependent pro-inflammatory activation and liver fibrosis. Mass spectrometry (interactome), co-immunoprecipitation, surface plasmon resonance, BRET, NanoBiT bioluminescence proximity assay, domain-mapping, Trpv1-/- mice Journal of Hepatology Medium 36669703
2024 Human SARM1 regulates proinflammatory cytokines in monocytes through both NADase-dependent and NADase-independent mechanisms: TNF mRNA induction is negatively regulated independently of NADase activity, while IL-1β secretion is inhibited via NADase-dependent suppression of pro-IL-1β expression AND via NADase-independent suppression of NLRP3 inflammasome processing. SARM1 knockout human monocytes, NADase-inactive SARM1 mutant, TLR4 stimulation, ELISA, RT-PCR, NLRP3 inflammasome assay iScience Medium 38832024
2015 SAG-dependent ubiquitin-proteasome system (UPS) targets SARM1 for ubiquitination and proteasomal degradation in hepatocellular carcinoma; upregulated SAG promotes high-molecular-weight ubiquitination of SARM1 (and Noxa), reducing their levels. SARM1 overexpression activates caspase-3 and caspase-9, reducing HCC cell viability. Co-IP of ubiquitinated SARM1, SAG overexpression/knockdown, caspase activation assay, HCC tissue immunohistochemistry Cell Death Discovery Low 27551463
2022 In a rat CMT2A model (Mfn2H361Y), deletion of Sarm1 rescues axonal, synaptic, muscle, and functional phenotypes, and also suppresses mitochondrial defects (number, size, cristae density) caused by the MFN2 mutation, revealing a positive feedback loop in which dysfunctional mitochondria activate SARM1 and activated SARM1 feeds back to exacerbate mitochondrial pathology. Sarm1-/- × Mfn2H361Y double-mutant rat model, neuromuscular junction histology, electron microscopy (mitochondria), behavioral testing The Journal of Clinical Investigation High 36287202

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature immunology 417 16964262
2013 Sarm1-mediated axon degeneration requires both SAM and TIR interactions. The Journal of neuroscience : the official journal of the Society for Neuroscience 308 23946415
2016 Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 272 26844829
2021 SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron 241 33657413
2015 Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell reports 165 25818290
2020 The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature 161 33053563
2021 SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling. Theranostics 153 33754056
2014 Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 150 25009267
2009 The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis. Journal of virology 142 19587044
2019 Cell Survival and Cytokine Release after Inflammasome Activation Is Regulated by the Toll-IL-1R Protein SARM. Immunity 125 31076360
2020 The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease. Current opinion in neurobiology 122 32311648
2019 Gene therapy targeting SARM1 blocks pathological axon degeneration in mice. The Journal of experimental medicine 118 30642945
2021 Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy. Brain : a journal of neurology 117 33964142
2020 SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration. The Journal of cell biology 116 32609299
2001 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 115 11386760
2016 SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proceedings of the National Academy of Sciences of the United States of America 109 27671644
2010 SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. European journal of immunology 103 20306472
2020 Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1. Cell reports 99 32755591
2020 Structural basis for SARM1 inhibition and activation under energetic stress. eLife 97 33185189
2020 cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons. Experimental neurology 90 32087251
2022 Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients. Molecular neurodegeneration 83 34991663
2012 T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell death and differentiation 72 23175186
2007 SARM: a novel Toll-like receptor adaptor, is functionally conserved from arthropod to human. Molecular immunology 71 17980913
2019 Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss. Acta neuropathologica communications 70 31661035
2018 Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Experimental eye research 68 29526794
2019 Sarm1 deletion reduces axon damage, demyelination, and white matter atrophy after experimental traumatic brain injury. Experimental neurology 67 31445042
2013 SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Molecular biology of the cell 64 23885119
2020 SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration. eLife 63 33107823
2019 Sarm1 Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice. Diabetes 63 31439642
2022 Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain. Proceedings of the National Academy of Sciences of the United States of America 60 35994671
2021 Live imaging reveals the cellular events downstream of SARM1 activation. eLife 60 34779400
2019 Structural Evidence for an Octameric Ring Arrangement of SARM1. Journal of molecular biology 60 31278906
2019 Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases. Cell chemical biology 60 31761689
2022 Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition. eLife 51 35098926
2021 Multiple domain interfaces mediate SARM1 autoinhibition. Proceedings of the National Academy of Sciences of the United States of America 49 33468661
2021 Social Media, Body Image and Resistance Training: Creating the Perfect 'Me' with Dietary Supplements, Anabolic Steroids and SARM's. Sports medicine - open 49 34757466
2022 A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model. The Journal of clinical investigation 48 36287202
2013 Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. Innate immunity 48 23751821
2019 SARM: From immune regulator to cell executioner. Biochemical pharmacology 46 30633870
2020 Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation. Scientific reports 45 33318563
2021 Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1. eLife 44 34870595
2015 SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactions. Biochimica et biophysica acta 44 26592460
2020 Passenger Mutations Confound Phenotypes of SARM1-Deficient Mice. Cell reports 43 32268088
2022 Multifaceted roles of SARM1 in axon degeneration and signaling. Frontiers in cellular neuroscience 40 36090788
2020 SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration. Life science alliance 40 32312889
2020 Identification of the first noncompetitive SARM1 inhibitors. Bioorganic & medicinal chemistry 40 32828421
2022 Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria. eLife 38 35285800
2010 Amphioxus SARM involved in neural development may function as a suppressor of TLR signaling. Journal of immunology (Baltimore, Md. : 1950) 38 20483721
2023 Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1. Journal of hepatology 35 36669703
2021 SARM1 signaling mechanisms in the injured nervous system. Current opinion in neurobiology 35 34175654
2021 Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed. Neuron 34 34384519
2018 The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1. Molecular and cellular biochemistry 34 30191480
2021 Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures. Acta neuropathologica communications 33 34001261
2021 Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Experimental neurology 33 34403688
2018 Celastrol attenuates incision-induced inflammation and pain associated with inhibition of the NF-κB signalling pathway via SARM. Life sciences 33 29750991
2024 SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease. Aging and disease 32 37307837
2021 SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration. Experimental neurology 31 33548217
2023 Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies. Molecular therapy. Nucleic acids 30 36950280
2022 Astrocytic SARM1 promotes neuroinflammation and axonal demyelination in experimental autoimmune encephalomyelitis through inhibiting GDNF signaling. Cell death & disease 29 36055989
2021 Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice. Experimental neurology 29 33460644
2019 SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease. The Journal of experimental medicine 29 30842236
2014 SARM regulates CCL5 production in macrophages by promoting the recruitment of transcription factors and RNA polymerase II to the Ccl5 promoter. Journal of immunology (Baltimore, Md. : 1950) 27 24711619
2020 Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. EMBO molecular medicine 26 31930715
2015 Telmisartan mediates anti-inflammatory and not cognitive function through PPAR-γ agonism via SARM and MyD88 signaling. Pharmacology, biochemistry, and behavior 26 26264163
2015 MMP-12-mediated by SARM-TRIF signaling pathway contributes to IFN-γ-independent airway inflammation and AHR post RSV infection in nude mice. Respiratory research 25 25652021
2018 HPV-transformed cells exhibit altered HMGB1-TLR4/MyD88-SARM1 signaling axis. Scientific reports 24 29472602
2015 Beyond TLR Signaling—The Role of SARM in Antiviral Immune Defense, Apoptosis & Development. International reviews of immunology 24 26268046
2016 A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice. The Journal of steroid biochemistry and molecular biology 23 27106747
2021 CRISPR/Cas9-mediated SARM1 knockout and epitope-tagged mice reveal that SARM1 does not regulate nuclear transcription, but is expressed in macrophages. The Journal of biological chemistry 22 34793837
2009 Effects of selective androgen receptor modulator (SARM) treatment in osteopenic female rats. Pharmaceutical research 22 19728047
2022 SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration. International journal of molecular sciences 20 35163535
2022 Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury. Proceedings of the National Academy of Sciences of the United States of America 19 36375051
2021 Peroxisome Proliferator-Activated Receptor Delta Agonist (PPAR- δ) and Selective Androgen Receptor Modulator (SARM) Abuse: Clinical, Analytical and Biological Data in a Case Involving a Poisonous Combination of GW1516 (Cardarine) and MK2866 (Ostarine). Toxics 19 34678947
2024 Augustus Waller's foresight realized: SARM1 in peripheral neuropathies. Current opinion in neurobiology 17 38852438
2021 Functional characterization of four TIR domain-containing adaptors, MyD88, TRIF, MAL, and SARM in mandarin fish Siniperca chuatsi. Developmental and comparative immunology 17 33933533
2021 The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems. Frontiers in immunology 17 34630431
2024 SARM1 regulates pro-inflammatory cytokine expression in human monocytes by NADase-dependent and -independent mechanisms. iScience 16 38832024
2023 SARM1 promotes the neuroinflammation and demyelination through IGFBP2/NF-κB pathway in experimental autoimmune encephalomyelitis mice. Acta physiologica (Oxford, England) 16 37186158
2013 UXT plays dual opposing roles on SARM-induced apoptosis. FEBS letters 16 24021647
2024 SARM1 regulates NAD+-linked metabolism and select immune genes in macrophages. The Journal of biological chemistry 15 38176648
2023 TIR-1/SARM1 inhibits axon regeneration and promotes axon degeneration. eLife 15 37083456
2022 SARM1 can be a potential therapeutic target for spinal cord injury. Cellular and molecular life sciences : CMLS 15 35224705
2022 SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection. Frontiers in molecular neuroscience 15 35493328
2022 SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice. Cell death & disease 15 35869039
2021 Expression of sterile-α and armadillo motif containing protein (SARM) in rheumatoid arthritis monocytes correlates with TLR2-induced IL-1β and disease activity. Rheumatology (Oxford, England) 15 33605409
2020 Sarm1 knockout protects against early but not late axonal degeneration in experimental allergic encephalomyelitis. PloS one 15 32584865
2015 Hm-MyD88 and Hm-SARM: two key regulators of the neuroimmune system and neural repair in the medicinal leech. Scientific reports 15 25880897
2024 Loss of Sarm1 reduces retinal ganglion cell loss in chronic glaucoma. Acta neuropathologica communications 13 38331947
2022 SARM1 participates in axonal degeneration and mitochondrial dysfunction in prion disease. Neural regeneration research 13 35259852
2022 A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1. Nature communications 13 36550129
2021 Sarm1 is Essential for Anesthesia-Induced Neuroinflammation and Cognitive Impairment in Aged Mice. Cellular and molecular neurobiology 13 33433724
2017 Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f. PloS one 13 29216311
2022 TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line. Scientific reports 12 35468924
2022 Distinct developmental and degenerative functions of SARM1 require NAD+ hydrolase activity. PLoS genetics 12 35737728
2022 Mitochondrial Localization of SARM1 in Acrylamide Intoxication Induces Mitophagy and Limits Neuropathy. Molecular neurobiology 12 36171479
2015 SAG-UPS attenuates proapoptotic SARM and Noxa to confer survival advantage to early hepatocellular carcinoma. Cell death discovery 12 27551463
2025 SARM1 deletion inhibits astrogliosis and BBB damage through Jagged-1/Notch-1/NF-κB signaling to improve neurological function after ischemic stroke. Neurobiology of disease 11 40089164
2022 Sarm1 knockout modifies biomarkers of neurodegeneration and spinal cord circuitry but not disease progression in the mSOD1G93A mouse model of ALS. Neurobiology of disease 11 35863521
2021 Acidic pH irreversibly activates the signaling enzyme SARM1. The FEBS journal 11 34213829
2020 A selective androgen receptor modulator SARM-2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys. Pharmacology research & perspectives 11 32030892

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