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Showing NLRP1 — NAC is a alias.

NLRP1

NACHT, LRR and PYD domains-containing protein 1 · UniProt Q9C000

Length
1473 aa
Mass
165.9 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRP1 is an innate immune sensor that nucleates an inflammasome platform to drive caspase-1-dependent maturation of IL-1β/IL-18 and pyroptotic cell death in response to diverse pathogen activities and cellular stresses (PMID:22753929, PMID:30872533). The receptor is held inactive by two coupled mechanisms: constitutive autoproteolysis within its FIIND domain at a conserved SF/S motif generating non-covalently associated fragments (PMID:22087307), and sequestration of the activating C-terminal fragment by DPP9, whose scaffolding and catalytic activities synergize to maintain autoinhibition (PMID:30291141). Cryo-EM of the NLRP1–DPP9 ternary complex shows DPP9 captures the C-terminal fragment only in the presence of full-length NLRP1, with the CT N-terminus inserting into the DPP9 active site, so that activation is set by the ratio of free CT to full-length protein (PMID:33731932, PMID:33731929). Activation converges on 'functional degradation': proteasomal destruction of the autoinhibitory N-terminal fragment is necessary and sufficient to liberate the C-terminal UPA-CARD fragment, which oligomerizes into a two-layered filament with an inner CARD core that recruits ASC and templates caspase-1 activation (PMID:30872533, PMID:33420033, PMID:33420028). This degradation is triggered by pathogen enzymes that cleave NLRP1 within a rapidly evolving 'tripwire' region—anthrax lethal toxin and the Shigella ubiquitin ligase IpaH7.8 (PMID:30872533), enteroviral 3C proteases cleaving at Glu130-Gly131 to expose an N-glycine degron processed by cullin-ZER1/ZYG11B (PMID:33093214, PMID:33410748), and coronavirus 3CL proteases cleaving at Q333 (PMID:35594856)—or by direct sensing: dsRNA binding to the LRR domain confers NACHT ATPase activity (PMID:33243852), and a human-specific disordered linker is hyperphosphorylated at Ser107 by ZAKα/p38 during ribotoxic stress from UVB, ribotoxins, potassium efflux, and oxidative nucleic acid damage (PMID:35857590, PMID:36315050, PMID:38175865). Patient-derived FIIND mutations that abrogate DPP9 binding and autoimmune-associated haplotypes cause inflammasome hyperactivation (PMID:30291141, PMID:23382179), and NLRP1 acts upstream of IL-18 to control systemic metabolism (PMID:26603191).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 Medium

    Established NLRP1 as a multidomain Ced-4-family protein with a CARD capable of engaging caspases and triggering cell death, framing it as a death-signaling scaffold before its inflammasome role was known.

    Evidence Co-immunoprecipitation, deletion mutagenesis, and cell death reporter assays in MCF7 cells

    PMID:11076957

    Open questions at the time
    • Caspase-2/-9 interactions did not establish the physiological caspase-1/IL-1β axis
    • Overexpression apoptosis may not reflect endogenous function
  2. 2011 High

    Identified FIIND autoproteolysis at the SF/S motif as a constitutive processing event, revealing the structural basis for the two-fragment architecture central to NLRP1 regulation.

    Evidence Bioinformatic ZU5-UPA modeling and site-directed mutagenesis with autoproteolysis assays

    PMID:22087307

    Open questions at the time
    • Functional consequence of cleavage for activation not yet defined
    • Did not establish how the cleaved fragments are kept inactive
  3. 2012 High

    Defined the NLRP1 inflammasome in vivo as required for anthrax lethal toxin-triggered caspase-1 activation, IL-1β release, and pyroptosis-driven lung injury, distinguishing it from NLRP3.

    Evidence NLRP1 knockout mice with lethal toxin challenge and lung injury model

    PMID:22753929

    Open questions at the time
    • Molecular mechanism by which lethal toxin activates NLRP1 not yet resolved
    • Mouse NLRP1B vs human NLRP1 differences unaddressed
  4. 2014 High

    Showed Toxoplasma gondii activates rodent NLRP1 to restrict parasite replication, linking allelic variation to pyroptosis sensitivity and establishing a pathogen sensing role.

    Evidence Nlrp1 knockdown and allele-transfer overexpression with T. gondii infection in rat macrophages

    PMID:24626226

    Open questions at the time
    • Direct molecular trigger from T. gondii not identified
    • Allelic determinants of sensitivity not mapped to specific residues
  5. 2015 High

    Connected NLRP1 to transcriptional control during ER stress (ATF4-driven induction) and to systemic metabolism, placing NLRP1 upstream of IL-18 in adiposity regulation.

    Evidence ChIP/promoter mutagenesis/CRISPR for ATF4 regulation; knockout/knock-in mouse metabolic phenotyping with IL-18 epistasis rescue

    PMID:26086088 PMID:26603191

    Open questions at the time
    • Mechanistic link between ER stress transcription and inflammasome assembly unclear
    • How IL-18 mediates metabolic effects not detailed
  6. 2018 High

    Identified DPP9 as an endogenous brake whose scaffolding and catalytic functions maintain NLRP1 inactivity, with patient mutations losing DPP9 binding causing hyperactivation.

    Evidence Proteomics, Co-IP, CRISPR deletion, DPP8/9 inhibition, and patient mutation validation

    PMID:30291141

    Open questions at the time
    • Structural basis of DPP9 sequestration not yet resolved
    • How DPP9 release couples to fragment liberation unknown
  7. 2019 High

    Unified NLRP1 activation under 'functional degradation', showing proteasomal destruction of the N-terminal fragment is necessary and sufficient to release the C-terminal activator across distinct triggers.

    Evidence Proteasome inhibition, reconstitution, and IpaH7.8 epistasis with caspase-1 readouts; DPP8/9 inhibitor allele panel and T. gondii comparison

    PMID:30872533 PMID:31383852

    Open questions at the time
    • Ubiquitin ligases for each trigger not all identified
    • Degron features driving degradation incompletely mapped
  8. 2020 High

    Distinguished direct sensing (dsRNA binding to LRR conferring NACHT ATPase activity) from protease-driven N-degron activation, establishing the LRR and the tripwire as parallel input modules.

    Evidence Biochemical dsRNA binding and ATPase assays with viral infection; enteroviral 3C cleavage mapping to Glu130-Gly131 with cullin-ZER1/ZYG11B genetics in primary airway cells

    PMID:33093214 PMID:33243852

    Open questions at the time
    • How dsRNA-induced ATPase activity leads to fragment release not resolved
    • Whether both inputs converge on identical downstream filament unaddressed
  9. 2021 High

    Cryo-EM of NLRP1–DPP9 complexes and the C-terminal filament revealed the structural logic of autoinhibition (CT sequestration requiring full-length NLRP1, ZU5-dependent assembly) and activation (CARD filament templating ASC recruitment).

    Evidence Cryo-EM of human/rat NLRP1-DPP9 ternary complexes with VbP co-structure; cryo-EM of NLRP1-CT/FIINDUPA-CARD assemblies with ASC speck assays

    PMID:33420028 PMID:33420033 PMID:33731929 PMID:33731932

    Open questions at the time
    • Dynamics of CT release from DPP9 in cells not directly visualized
    • Stoichiometry of in vivo filament assembly uncertain
  10. 2021 High

    Extended viral activation to a broad picornaviral protease tripwire and identified a protease-independent route via KSHV ORF45 disrupting a Linker1-UPA autoinhibitory interface, revealing DPP9-independent silencing.

    Evidence Protease cleavage and inflammasome assays with evolutionary analysis; Co-IP and domain mutagenesis for ORF45-Linker1 with species comparison

    PMID:33410748 PMID:35618833

    Open questions at the time
    • Full set of host targets within the evolving tripwire not enumerated
    • Relationship between Linker1-UPA silencing and DPP9 sequestration unclear
  11. 2022 High

    Defined the ribotoxic stress response as a sensing pathway in which ZAKα/p38 hyperphosphorylate a human-specific disordered linker (Ser107), with the linker sufficient to confer RSR sensitivity and feeding into ubiquitination and N-terminal degradation.

    Evidence Kinase assays, S107 mutagenesis, NLRP1DR-CARD8 domain swap, ZAKα/p38 knockout/inhibition; ubiquitination and pathway epistasis with pyroptosis readouts

    PMID:35857590 PMID:36315050

    Open questions at the time
    • Ubiquitin ligase recognizing phosphorylated NLRP1 not identified
    • How phosphorylation triggers N-terminal degradation mechanistically unclear
  12. 2022 High

    Established coronavirus 3CL proteases as NLRP1 activators (cleaving at Q333) that also inactivate Gasdermin D to redirect cell death to caspase-3/GSDME pyroptosis, integrating NLRP1 into antiviral defense and viral counter-strategies.

    Evidence In vitro cleavage mapping, NLRP1 knockout cells, SARS-CoV-2 infection of lung epithelia, multiple coronavirus proteases

    PMID:35594856

    Open questions at the time
    • In vivo relevance to COVID-19 pathology not established here
    • Balance between GSDMD and GSDME outcomes context-dependent
  13. 2023 Medium

    Generalized RSR-driven NLRP1 activation to diverse stressors (diphtheria toxin, oxidative DNA damage from poly(dA:dT), protein folding stress) all converging on ZAKα/p38 or coupled to DPP9 ligand accumulation, defining NLRP1 as an integrator of ribosomal and proteostatic stress.

    Evidence NLRP1/ZAKα knockout and inhibitor studies in keratinocytes and 3D skin; pathway-exclusion genetics; protein folding stress inducers with DPP9 displacement assays

    PMID:36649711 PMID:36693106 PMID:37642997

    Open questions at the time
    • Precise upstream lesion sensed by ZAKα across stressors not unified
    • Quantitative thresholds linking stress to activation undefined
  14. 2024 High

    Showed potassium efflux activates NLRP1 indirectly through ribosome elongation inhibition and ZAKα/p38, distinguishing the K+ threshold for NLRP1 from NLRP3 and tying ionic perturbation to the RSR sensing axis.

    Evidence K+ manipulation, ZAKα knockout, ZAKα/p38 inhibition, ionophore screen, phosphorylation and pyroptosis assays in keratinocytes

    PMID:38175865

    Open questions at the time
    • Molecular link between K+ loss and ribosome stalling not fully defined
    • Cell-type specificity of K+-NLRP1 coupling unaddressed
  15. 2024 Medium

    Implicated NLRP1 in tissue-specific disease and homeostatic contexts—Schwann cell C5aR1-NLRP1 in pain, NLRP1-mTOR in stress-related depression, and ZAKα/p38-NLRP1 with LRRFIP1/FLII inhibitors in hematopoiesis—broadening its physiological footprint.

    Evidence C5aR1 silencing and pain behavior; NLRP1-mTOR Co-IP and Nlrp1a knockdown with rapamycin; zebrafish nlrp1 inhibition and LRRFIP1/FLII interaction studies

    PMID:37675820 PMID:38178196 PMID:39587068

    Open questions at the time
    • These tissue contexts rely largely on single labs and rodent/zebrafish models
    • Direct NLRP1-mTOR interaction not structurally validated
    • LRRFIP1/FLII inhibitory mechanism not mechanistically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The complete set of ubiquitin ligases and degron-recognition machinery linking each upstream trigger (phosphorylation, cleavage, dsRNA) to N-terminal fragment degradation remains incompletely defined.
  • Trigger-specific E3 ligases not all identified
  • How distinct inputs funnel into a common degradation outcome not unified
  • Structural snapshot of the activating transition in cells lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0005198 structural molecule activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0003723 RNA binding 1 GO:0140110 transcription regulator activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1643685 Disease 2
Partners
ASCATF4CASP1DPP9FLIILRRFIP1MAPK14ZAK
Complex memberships
NLRP1 inflammasomeNLRP1-DPP9 inhibitory complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NLRP1 (DEFCAP) was identified as a novel member of the mammalian Ced-4 family containing a pyrin-like motif, CARD, nucleotide-binding domain, and leucine-rich repeats. In vitro co-immunoprecipitation showed DEFCAP-L and -S interact with caspase-2 (strong) and caspase-9 (weak). Overexpression of full-length DEFCAP-L (but not -S) induced apoptosis in MCF7 cells; deletion mutagenesis showed the LRR/CARD fragment is constitutively active and killing is blocked by caspase inhibitors, indicating the CARD is critical for apoptosis-inducing activity. Co-immunoprecipitation, transient overexpression, deletion mutagenesis, cell death reporter assay The Journal of biological chemistry Medium 11076957
2011 NLRP1 and CARD8 undergo autoproteolytic cleavage at a conserved SF/S motif within the FIIND domain. Bioinformatics revealed structural similarity to the ZU5-UPA domain of PIDD. Site-directed mutagenesis showed the second serine of the SF/S motif is required for autoproteolysis; conserved glutamic acid and histidine residues nearby also regulate cleavage efficiency. Bioinformatics/structural modeling, site-directed mutagenesis, autoproteolysis assay PloS one High 22087307
2012 NLRP1 knockout mice demonstrated that the NLRP1 inflammasome is required for anthrax lethal toxin-triggered caspase-1 activation, IL-1β release, and pyroptotic cell death. This cell death escalates to cause acute lung injury independent of IL-1β production but dependent on caspase-1. Muramyl dipeptide-mediated inflammasome formation was not dependent on NLRP1 but on NLRP3. NLRP1 knockout mouse, anthrax lethal toxin challenge, caspase-1 activity assay, IL-1β measurement, lung injury model Journal of immunology High 22753929
2013 NLRP1 haplotypes associated with autoimmune disease (sharing L155H and M1184V substitutions) cause increased processing of pro-IL-1β to mature IL-1β under basal and TLR-stimulated conditions in primary human monocytes, without altering NLRP1 RNA or protein levels, indicating that the multivariant polypeptide itself has altered function. Primary human monocyte functional assay, IL-1β ELISA, genotyping Proceedings of the National Academy of Sciences of the United States of America Medium 23382179
2015 Transcription factor ATF4 directly binds the NLRP1 promoter during ER stress and upregulates NLRP1 expression. Both IRE1α and PERK pathways (but not ATF6) modulate NLRP1 gene expression. This was established by mutagenesis, chromatin immunoprecipitation, and CRISPR-Cas9-mediated genome editing. ChIP, promoter mutagenesis, CRISPR-Cas9 genome editing, qRT-PCR PloS one High 26086088
2015 Mice lacking NLRP1 phenocopy IL-18 knockout mice, exhibiting spontaneous obesity and metabolic syndrome due to intrinsic lipid accumulation. Mice with an activating NLRP1 mutation have decreased adiposity and increased plasma IL-18. Genetic deletion of IL-18 prevents the fatal cachexia caused by NLRP1 hyperactivation on high-fat diet, placing NLRP1 upstream of IL-18 in metabolic regulation. NLRP1 knockout and knock-in mouse models, metabolic phenotyping, genetic epistasis (IL-18 deletion rescue) Cell metabolism High 26603191
2019 Proteasome-mediated degradation of the NLRP1B N-terminal fragment is both necessary and sufficient for NLRP1B activation. Anthrax lethal toxin cleavage triggers this degradation, liberating the C-terminal fragment as a potent caspase-1 activator. Shigella flexneri ubiquitin ligase IpaH7.8 also induces NLRP1B degradation and activation by the same mechanism, establishing 'functional degradation' as a unified activation mechanism. Proteasome inhibitor studies, reconstitution assays, epistasis with IpaH7.8 (Shigella effector), caspase-1 activation assay Science High 30872533
2018 DPP9 was identified as an endogenous inhibitor of the human NLRP1 inflammasome via proteomics screen. DPP9 interacts with the FIIND domain of NLRP1. Its scaffolding function and catalytic activity act synergistically to maintain NLRP1 in an inactive state. A patient-derived germline missense mutation in the NLRP1 FIIND domain abrogates DPP9 binding and leads to inflammasome hyperactivation. Proteomics screen, Co-IP, CRISPR/Cas9 deletion, DPP8/9 small molecule inhibition, ASC speck formation assay, IL-1β secretion assay, mutagenesis The Journal of biological chemistry High 30291141
2019 DPP8/9 inhibitors (e.g., Val-boroPro) activate all functional rodent NLRP1 alleles. NLRP1 allele sensitivities to DPP8/9 inhibitor-induced and Toxoplasma gondii-induced pyroptosis are strikingly similar, suggesting DPP8/9 inhibition phenocopies a key T. gondii activity. Pyroptosis assays across multiple rodent NLRP1 alleles, DPP8/9 inhibitor treatment, T. gondii infection comparison Cell death & disease Medium 31383852
2020 Human NLRP1 directly binds double-stranded RNA through its leucine-rich repeat domain, and this interaction causes the NACHT domain to gain ATPase activity. SFV replication and dsRNA formation are required to engage the NLRP1 inflammasome; delivery of long dsRNA alone is sufficient to trigger activation. Biochemical binding assays, ATPase activity assay, mutagenesis of LRR domain, viral infection model, dsRNA transfection Science High 33243852
2020 Enteroviral 3C proteases directly cleave human NLRP1 at a single site (Glu130-Gly131), triggering N-glycine-mediated degradation of the autoinhibitory N-terminal fragment via the cullin-ZER1/ZYG11B complex. This liberates the activating C-terminal fragment, leading to inflammasome activation and IL-18 secretion in primary human airway epithelial cells. In vitro protease cleavage assay, N-degron pathway genetic manipulation (cullin-ZER1/ZYG11B), primary human airway epithelial cell infection, IL-18 ELISA Science High 33093214
2021 Cryo-EM structures of the human NLRP1-DPP9 complex reveal a ternary complex comprising DPP9, full-length NLRP1, and the NLRP1 C-terminal fragment (CT). DPP9 sequesters the NLRP1 CT only when full-length NLRP1 is present, suggesting activation is regulated by the ratio of CT to full-length NLRP1. The N-terminus of the NLRP1 CT inserts into the DPP9 active site; Val-boroPro (VbP) disrupts this interaction and accelerates N-terminal fragment degradation. Cryo-EM structure determination, cell-based inflammasome activation assays, co-expression rescue experiments, VbP inhibitor co-structure Nature High 33731932
2021 Cryo-EM/biochemical structures of rat NLRP1-DPP9 show a 2:1 complex containing autoinhibited full-length NLRP1 and an active UPA-CARD fragment. The ZU5 domain is required for both NLRP1 autoinhibition and assembly of the 2:1 complex. Complex formation prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated autoinhibition. Both NLRP1 binding and DPP9 enzymatic activity are required to suppress NLRP1 in human cells. Cryo-EM, biochemical reconstitution, structure-guided mutagenesis, cell-based functional assays Nature High 33731929
2021 Cryo-EM structures of NLRP1-CT and CARD8-CT assemblies show that CARDs form central helical filaments promoted by oligomerized but flexibly-linked UPAs. NLRP1-CARD filaments drive ASC speck formation; NLRP1-FIINDUPA enhances oligomerization. An exterior CARD dimerization doubles NLRP1CARD filament thickness uniquely among known CARD filaments. ASC uses opposing surfaces to recruit NLRP1 vs. caspase-1. Cryo-EM (3.7 Å), biochemical reconstitution, cell-based ASC speck formation assays Nature communications High 33420033
2021 The activating domains (FIINDUPA-CARD) of NLRP1 self-oligomerize to form a two-layered filament with an inner CARD core surrounded by an outer FIINDUPA ring. Self-assembled NLRP1-CARD filaments drive ASC speck formation in human cells, and NLRP1-FIINDUPA oligomers greatly enhance this. Structural differences in NLRP1-CARD vs. CARD8-CARD enable selective recruitment of ASC vs. pro-caspase-1, respectively. Cryo-EM (3.7 Å), recombinant protein reconstitution, cell-based ASC speck assay Nature communications High 33420028
2021 Diverse viral proteases from picornaviruses cleave human NLRP1 within a rapidly evolving 'tripwire' region, leading to host-specific and virus-specific activation of the NLRP1 inflammasome. The mechanism parallels anthrax LeTx-driven NLRP1B degradation; cleavage leads to N-terminal degradation and liberation of the bioactive C-terminal domain. Protease cleavage assays, inflammasome activation assays, evolutionary analysis of cleavage sites eLife High 33410748
2021 KSHV ORF45 protein activates human NLRP1 inflammasome independently of proteolytic cleavage, by binding the Linker1 region (between PYD and NACHT domains). At steady state, Linker1 interacts with the UPA subdomain to silence NLRP1 in auto-inhibitory complexes independent of DPP9. ORF45 binding to Linker1 displaces UPA from the Linker1-UPA complex, releasing the C-terminal domain for inflammasome assembly. This activation mechanism is conserved in primates but not murine NLRP1b. Co-IP, domain mutagenesis, inflammasome activation assays, species comparison Nature immunology High 35618833
2022 Human NLRP1 senses the ribotoxic stress response (RSR) triggered by UVB and ribotoxins. ZAKα kinase and its downstream effector p38 directly hyperphosphorylate a human-specific disordered linker region (NLRP1DR). Mutating a single ZAKα phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in keratinocytes. Fusing NLRP1DR to CARD8 (which is insensitive to RSR) creates a minimal RSR sensor, confirming NLRP1DR is sufficient. Kinase activity assay, site-directed mutagenesis, domain-swap experiment (NLRP1DR-CARD8), ZAKα/p38 knockout/inhibition, pyroptosis assay Science High 35857590
2022 p38 MAPK directly phosphorylates NLRP1; serine 107 in the linker region is critical for activation by ribotoxic stress and alphavirus infection. This phosphorylation is followed by ubiquitination of NLRP1 PYD, N-terminal degradation, and inflammasome nucleation. Activation by nanobody-mediated ubiquitination, viral proteases, or DPP9 inhibition was independent of p38 activity, establishing p38 as a specific signaling hub for stress-induced activation. Kinase assay, site-directed mutagenesis (S107), ubiquitination assay, pathway epistasis (p38 inhibitors, ZAKα KO), pyroptosis assay The Journal of experimental medicine High 36315050
2022 SARS-CoV-2 3CL protease cleaves human NLRP1 at Q333, triggering inflammasome assembly, cell death, and limitation of infectious viral particle production in human lung epithelial cells. Multiple coronavirus 3CL proteases activate NLRP1 by this mechanism. 3CL proteases also inactivate Gasdermin D, redirecting pyroptosis to caspase-3/GSDME-mediated alternative pyroptosis. In vitro protease cleavage assay, NLRP1 knockout cell lines, SARS-CoV-2 infection of lung epithelial cells, cytokine secretion, cell death assays Molecular cell High 35594856
2023 Diphtheria toxin activates ribotoxic stress response via ZAKα/p38-driven hyperphosphorylation of NLRP1, triggering NLRP1 inflammasome-dependent IL-1β and IL-18 secretion in primary human keratinocytes. NLRP1 deletion abrogates cytokine secretion. ZAKα inhibition was more protective than caspase-1 inhibition in a 3D skin model of cutaneous diphtheria, demonstrating ZAKα functions both upstream of NLRP1 and in non-inflammasome cell death. NLRP1 and ZAKα knockout/inhibition, cytokine assay, 3D skin model, pharmacologic ZAKα and caspase-1 inhibition The Journal of experimental medicine High 37642997
2023 Poly(dA:dT) activates the NLRP1 inflammasome in human keratinocytes via oxidative nucleic acid damage and cellular stress that activates MAP3 kinases including ZAKα converging on p38, rather than through dsRNA intermediates or AIM2/cGAS-STING-NLRP3 pathways. Conventional linear dsDNA fails to activate NLRP1. NLRP1 knockout, AIM2 and cGAS-STING pathway genetic ablation, ZAKα/p38 inhibitor treatment, caspase-1 activation assay, cytokine secretion Proceedings of the National Academy of Sciences of the United States of America High 36693106
2023 Several agents that interfere with protein folding (aminopeptidase inhibitors, chaperone inhibitors, unfolded protein response inducers) accelerate NLRP1 N-terminal fragment degradation. However, the released CT fragments are sequestered by DPP9 and do not form inflammasomes unless DPP9-binding ligands are also present to disrupt CT-DPP9 complexes. This demonstrates NLRP1 detects a specific perturbation involving both protein folding stress and DPP9 ligand accumulation. Protein folding stress inducers, proteasome assay, DPP9 binding/displacement assay, inflammasome activation assay Cell reports Medium 36649711
2024 Nigericin activates the NLRP1 inflammasome in human keratinocytes via potassium efflux-dependent inhibition of ribosome elongation, activating RSR sensor kinase ZAKα and downstream p38/JNK, and hyperphosphorylating the NLRP1 linker domain. Extracellular K+ supplementation, ZAKα knockout, or ZAKα/p38 inhibitors block nigericin-induced NLRP1 pyroptosis. Greater K+ depletion is required to activate ZAKα-NLRP1 than NLRP3. K+ manipulation, ZAKα knockout, pharmacologic ZAKα/p38 inhibition, ionophore panel screen, pyroptosis assay, NLRP1 phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 38175865
2014 In rat macrophages, Toxoplasma gondii activates the NLRP1 inflammasome to induce pyroptosis, IL-1β/IL-18 processing, and inhibition of parasite proliferation. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death; overexpression of the NLRP1 variant from sensitive macrophages in resistant cells sensitized them to pyroptosis. NLRP1 knockdown (siRNA), NLRP1 overexpression (allele transfer), T. gondii infection, pyroptosis/cytokine assay PLoS pathogens High 24626226
2016 Heme oxygenase-1 (HO-1) suppresses NLRP1 inflammasome-induced neuronal death after spinal cord injury by inhibiting expression of activating transcription factor 4 (ATF4), a transcription factor that regulates NLRP1 expression. This was demonstrated by immunoprecipitation showing NLRP1 inflammasome formation in spinal cord neurons, and by AAV-mediated HO-1 overexpression reducing NLRP1 expression and neuronal death in vivo and in vitro. AAV-mediated HO-1 overexpression, immunoprecipitation (NLRP1 complex), ATF4 expression analysis, neuronal death quantification Journal of neuroinflammation Medium 26925775
2023 NLRP1 interacts with mTOR by co-immunoprecipitation in hippocampal neurons; chronic social defeat stress facilitates this interaction and promotes autophagy impairment. Nlrp1a knockdown inhibited PI3K/AKT/mTOR signaling, rescued impaired autophagy, and ameliorated depressive-like behaviors. Rapamycin (mTOR inhibitor/autophagy inducer) abolished NLRP1 inflammasome-driven inflammation. Co-immunoprecipitation (NLRP1-mTOR), AAV-mediated Nlrp1a knockdown, rapamycin treatment, western blot, behavioral assays Journal of neuroinflammation Medium 38178196
2024 In a mouse model of endometriosis, Schwann cell C5aR1 activates the NLRP1 inflammasome, leading to IL-1β release. Silencing C5aR1 in Schwann cells blocked C5a-induced NLRP1 inflammasome activation. IL-1β from Schwann cells recruits macrophages to peripheral nerves, increases oxidative stress, and activates TRPA1, causing widespread pain. C5aR1 siRNA silencing in Schwann cells, NLRP1 inflammasome activation assay, IL-1β measurement, macrophage recruitment assay, pain behavior in mouse model Nature communications Medium 39587068
2023 ZAKα/p38 kinase signaling activates the NLRP1 inflammasome in the context of erythroid differentiation, causing ribosomal stress-mediated NLRP1 phosphorylation and assembly. LRRFIP1 and FLII were identified as endogenous inhibitors of the NLRP1 inflammasome in hematopoietic cells, acting independently of DPP9. Genetic inhibition of Nlrp1 in zebrafish reduced neutrophils and increased erythrocytes. Zebrafish nlrp1 genetic inhibition, identification of LRRFIP1/FLII as NLRP1 inhibitors by interaction studies, ZAKα/p38 phosphorylation assay, hematopoietic differentiation assay EMBO molecular medicine Medium 37675820

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease. Molecular neurodegeneration 414 26939933
2013 Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell death & disease 390 24008734
2019 Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes. Science (New York, N.Y.) 308 30872533
2014 Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. Cell death & disease 295 25144717
2014 Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma. Proceedings of the National Academy of Sciences of the United States of America 264 25024200
2020 Human NLRP1 is a sensor for double-stranded RNA. Science (New York, N.Y.) 250 33243852
2012 NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. Journal of immunology (Baltimore, Md. : 1950) 220 22753929
2015 The NLRP1 inflammasomes. Immunological reviews 197 25879281
2020 Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science (New York, N.Y.) 196 33093214
2018 Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. The Journal of biological chemistry 189 30291141
2020 NLRP1 inflammasome contributes to chronic stress-induced depressive-like behaviors in mice. Journal of neuroinflammation 175 32513185
2011 CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PloS one 175 22087307
2016 A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Annals of the rheumatic diseases 170 27965258
2021 DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature 169 33731932
2013 NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome. Proceedings of the National Academy of Sciences of the United States of America 166 23382179
2018 NLRP1 and NLRP3 inflammasomes mediate LPS/ATP‑induced pyroptosis in knee osteoarthritis. Molecular medicine reports 151 29393464
2020 The NLRP1 and CARD8 inflammasomes. Immunological reviews 150 32558991
2015 IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell metabolism 148 26603191
2022 ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science (New York, N.Y.) 146 35857590
2021 Diverse viral proteases activate the NLRP1 inflammasome. eLife 144 33410748
2015 The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis. Journal of immunology (Baltimore, Md. : 1950) 139 25725098
2021 Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature 127 33731929
2022 Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells. Molecular cell 123 35594856
2000 Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins. The Journal of biological chemistry 122 11076957
2014 Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLoS pathogens 116 24626226
2021 CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage. Stroke 107 34719258
2019 The Role of Neuronal NLRP1 Inflammasome in Alzheimer's Disease: Bringing Neurons into the Neuroinflammation Game. Molecular neurobiology 105 31111399
2019 miR-590-3p Inhibits Pyroptosis in Diabetic Retinopathy by Targeting NLRP1 and Inactivating the NOX4 Signaling Pathway. Investigative ophthalmology & visual science 105 31618425
2022 P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection. The Journal of experimental medicine 93 36315050
2020 NLRP3 and NLRP1 inflammasomes are up-regulated in patients with mesial temporal lobe epilepsy and may contribute to overexpression of caspase-1 and IL-β in sclerotic hippocampi. Brain research 89 33385378
2020 The NLRP1 Inflammasome in Human Skin and Beyond. International journal of molecular sciences 77 32640751
2019 Silibinin Downregulates the NF-κB Pathway and NLRP1/NLRP3 Inflammasomes in Monocytes from Pregnant Women with Preeclampsia. Molecules (Basel, Switzerland) 77 31010153
2017 Mechanisms of NLRP1-Mediated Autoinflammatory Disease in Humans and Mice. Journal of molecular biology 77 28733143
2021 Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8. Nature communications 74 33420028
2019 DPP8/9 inhibitors are universal activators of functional NLRP1 alleles. Cell death & disease 74 31383852
2012 NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis and rheumatism 74 21976003
2014 Genetic variations of NLRP1: susceptibility in psoriasis. The British journal of dermatology 72 24909542
2013 Deregulated NLRP3 and NLRP1 inflammasomes and their correlations with disease activity in systemic lupus erythematosus. The Journal of rheumatology 72 24334646
2021 The Role of NLRP1, NLRP3, and AIM2 Inflammasomes in Psoriasis: Review. International journal of molecular sciences 70 34072753
2021 Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes. Nature communications 68 33420033
2021 The Ferroptosis-NLRP1 Inflammasome: The Vicious Cycle of an Adverse Pregnancy. Frontiers in cell and developmental biology 65 34490257
2016 Heme oxygenase-1 promotes neuron survival through down-regulation of neuronal NLRP1 expression after spinal cord injury. Journal of neuroinflammation 61 26925775
2021 Human NLRP1: From the shadows to center stage. The Journal of experimental medicine 57 34910085
2017 Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis. Scientific reports 52 28623311
2021 Formulated Chinese medicine Shaoyao Gancao Tang reduces NLRP1 and NLRP3 in Alzheimer's disease cell and mouse models for neuroprotection and cognitive improvement. Aging 51 34106880
2020 Overexpression of MicroRNA-9a-5p Ameliorates NLRP1 Inflammasome-mediated Ischemic Injury in Rats Following Ischemic Stroke. Neuroscience 51 31954830
2015 Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression during Endoplasmic Reticulum Stress. PloS one 50 26086088
2023 NLRP1- A CINDERELLA STORY: a perspective of recent advances in NLRP1 and the questions they raise. Communications biology 47 38104185
2013 Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes. Journal of immunology (Baltimore, Md. : 1950) 47 24337744
2023 Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis. The Journal of experimental medicine 46 37642997
2021 Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment. Cell death and differentiation 46 34625662
2024 Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice. Journal of neuroinflammation 42 38178196
2022 KSHV-encoded ORF45 activates human NLRP1 inflammasome. Nature immunology 40 35618833
2022 NLRP1 Inflammasomes: A Potential Target for the Treatment of Several Types of Brain Injury. Frontiers in immunology 40 35707533
2023 Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT). Proceedings of the National Academy of Sciences of the United States of America 39 36693106
2024 Role of the NLRP1 inflammasome in skin cancer and inflammatory skin diseases. The British journal of dermatology 38 37889986
2023 Phosphatidylethanolamine alleviates OX-LDL-induced macrophage inflammation by upregulating autophagy and inhibiting NLRP1 inflammasome activation. Free radical biology & medicine 38 37660837
2021 Curcumin Alleviates Cerebral Ischemia-reperfusion Injury by Inhibiting NLRP1-dependent Neuronal Pyroptosis. Current neurovascular research 37 34109908
2009 Fine-mapping of vitiligo susceptibility loci on chromosomes 7 and 9 and interactions with NLRP1 (NALP1). The Journal of investigative dermatology 37 19727120
2017 Downregulated NLRP3 and NLRP1 inflammasomes signaling pathways in the development and progression of type 1 diabetes mellitus. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 28783585
2019 Hippocampal PKR/NLRP1 Inflammasome Pathway Is Required for the Depression-Like Behaviors in Rats with Neuropathic Pain. Neuroscience 35 31125603
2020 NLRP1 and NLRP3 inflammasomes as a new approach to skin carcinogenesis. Oncology letters 34 32194656
2013 Polymorphisms in NLRP1 gene and susceptibility to autoimmune thyroid disease. Autoimmunity 33 23374100
2017 NLRP1 Overexpression Is Correlated with the Tumorigenesis and Proliferation of Human Breast Tumor. BioMed research international 32 29214170
2023 Chronic hypoxia of endothelial cells boosts HIF-1α-NLRP1 circuit in Alzheimer's disease. Free radical biology & medicine 31 37245530
2021 NLRP1 inflammasome involves in learning and memory impairments and neuronal damages during aging process in mice. Behavioral and brain functions : BBF 31 34920732
2019 Expression of inflammasomes NLRP1, NLRP3 and AIM2 in different pathologic classification of lupus nephritis. Clinical and experimental rheumatology 31 31694740
2023 Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation. Cell reports 30 36649711
2022 The Expression of Inflammasomes NLRP1 and NLRP3, Toll-Like Receptors, and Vitamin D Receptor in Synovial Fibroblasts From Patients With Different Types of Knee Arthritis. Frontiers in immunology 29 35126351
2021 Progesterone and vitamin D downregulate the activation of the NLRP1/NLRP3 inflammasomes and TLR4-MyD88-NF-κB pathway in monocytes from pregnant women with preeclampsia. Journal of reproductive immunology 29 33578174
2023 The NLRP1 inflammasome in skin diseases. Frontiers in immunology 28 36911693
2020 Propofol Attenuates Inflammatory Damage via Inhibiting NLRP1-Casp1-Casp6 Signaling in Ischemic Brain Injury. Biological & pharmaceutical bulletin 28 32999158
2019 Inhibition of NOX2-NLRP1 signaling pathway protects against chronic glucocorticoids exposure-induced hippocampal neuronal damage. International immunopharmacology 28 31255881
2019 Polymorphisms in NLRP1 Gene Are Associated with Type 1 Diabetes. Journal of diabetes research 28 31396539
2021 Naofucong Ameliorates High Glucose Induced Hippocampal Neuron Injury Through Suppressing P2X7/NLRP1/Caspase-1 Pathway. Frontiers in pharmacology 26 34093185
2020 To protect or adversely affect? The dichotomous role of the NLRP1 inflammasome in human disease. Molecular aspects of medicine 26 32359693
2019 The NLRP1 Inflammasome Pathway Is Silenced in Cutaneous Squamous Cell Carcinoma. The Journal of investigative dermatology 26 30738816
2024 Mechanistic basis for potassium efflux-driven activation of the human NLRP1 inflammasome. Proceedings of the National Academy of Sciences of the United States of America 25 38175865
2022 NLRP1 Inflammasome Activation in Keratinocytes: Increasing Evidence of Important Roles in Inflammatory Skin Diseases and Immunity. The Journal of investigative dermatology 25 35550825
2021 NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes. Cell reports 25 34038731
2021 Neuroinflammation in Alzheimer's Disease: Focus on NLRP1 and NLRP3 Inflammasomes. Current protein & peptide science 25 34530705
2022 SOCE-mediated NFAT1-NOX2-NLRP1 inflammasome involves in lipopolysaccharide-induced neuronal damage and Aβ generation. Molecular neurobiology 24 35286582
2020 Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. Biochemical pharmacology 24 32059841
2022 The NLRP1 Inflammasome Induces Pyroptosis in Human Corneal Epithelial Cells. Investigative ophthalmology & visual science 23 35238869
2018 Inhibition of ER stress-related IRE1α/CREB/NLRP1 pathway promotes the apoptosis of human chronic myelogenous leukemia cell. Molecular immunology 23 30055408
2018 NLRP1 promotes TGF-β1-induced myofibroblast differentiation in neonatal rat cardiac fibroblasts. Journal of molecular histology 23 30120609
2015 Nlrp1 inflammasome is downregulated in trauma patients. Journal of molecular medicine (Berlin, Germany) 23 26232934
2023 Skin Colonization with S. aureus Can Lead to Increased NLRP1 Inflammasome Activation in Patients with Atopic Dermatitis. The Journal of investigative dermatology 22 36736455
2022 Ginsenoside Rg1 alleviates learning and memory impairments and Aβ disposition through inhibiting NLRP1 inflammasome and autophagy dysfunction in APP/PS1 mice. Molecular medicine reports 22 36367174
2012 NLRP1, a regulator of innate immunity associated with vitiligo. Pigment cell & melanoma research 22 22117610
2024 Eriocitrin ameliorates hepatic fibrosis and inflammation: The involvement of PPARα-mediated NLRP1/NLRC4 inflammasome signaling cascades. Journal of ethnopharmacology 21 39557108
2023 Inhibition of NLRP1 inflammasome improves autophagy dysfunction and Aβ disposition in APP/PS1 mice. Behavioral and brain functions : BBF 21 37055801
2023 Toxoplasma gondii Induces Pyroptosis in Human Placental Trophoblast and Amniotic Cells by Inducing ROS Production and Activation of Cathepsin B and NLRP1/NLRP3/NLRC4/AIM2 Inflammasome. The American journal of pathology 21 37741453
2022 Thioredoxin-1 inhibits amyloid-β25-35-induced activation of NLRP1/caspase-1/GSDMD pyroptotic pathway in PC12 cells. Molecular biology reports 21 35072836
2020 Inflammasome activation by NLRP1 and NLRC4 in patients with coronary stenosis. Immunobiology 21 32276737
2024 Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis. Nature communications 20 39587068
2020 Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma. Cancers 20 32899791
2018 Differential mRNA expression of inflammasome genes NLRP1 and NLRP3 in abdominal aneurysmal and occlusive aortic disease. Therapeutic advances in cardiovascular disease 20 29528779
2023 Tripping the wire: sensing of viral protease activity by CARD8 and NLRP1 inflammasomes. Current opinion in immunology 19 37311351
2023 ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome. EMBO molecular medicine 18 37675820

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