Affinage

NLRX1

NLR family member X1 · UniProt Q86UT6

Length
975 aa
Mass
107.6 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRX1 is a mitochondrially targeted NLR-family protein that acts as a broad negative regulator of innate antiviral and inflammatory signaling while controlling mitochondrial homeostasis (PMID:18200010, PMID:21703540, PMID:22749352). An N-terminal leader sequence directs NLRX1 across the inner membrane into the mitochondrial matrix in a membrane-potential-dependent manner and is cleaved to yield the mature protein, which engages the complex III subunit UQCRC2 to drive mitochondrial ROS production (PMID:19692591). NLRX1 dampens type I interferon induction through two parallel sensing pathways: it binds MAVS to disrupt RIG-I–MAVS coupling (PMID:18200010), and it sequesters STING away from TBK1 to block cytosolic DNA sensing (PMID:27078069); in the MAVS axis it can further recruit PCBP2 to drive K48-linked polyubiquitination and proteasomal degradation of MAVS via its NOD domain (PMID:28956771). It also restrains NF-κB signaling through a signal-dependent switch between TRAF6 and the IKK complex, inhibiting IKK phosphorylation downstream of TLR/LPS (PMID:21703540, PMID:21703539). Beyond immune suppression, NLRX1 couples to the mitochondrial quality-control machinery: it complexes with TUFM to promote autophagy and LC3-associated phagocytosis through ATG5–ATG12–ATG16L1 (PMID:22749352, PMID:30559741), and during mitochondrial protein import stress it is retained in the cytosol where it recruits the ER protein RRBP1 to drive PINK1-independent LC3 lipidation and mitophagy, a function that also operates in skeletal muscle during exercise (PMID:35752171). The C-terminal LRR region forms a hexamer and binds RNA, and is the docking site for small-molecule lipid ligands (PMID:22386589, PMID:26714018). A crystal-clear caveat exists in the field: an independently generated Nlrx1−/− strain showed normal antiviral responses and traced part of the original MAVS-inhibition signal to a luciferase reporter artifact (PMID:23212541, PMID:22718770). NLRX1 additionally regulates mitochondrial RNA processing via FASTKD5 (PMID:29932989), apoptotic balance via SARM1 (PMID:30191480), and calcium-induced permeability transition pore opening at the inner membrane (PMID:40536683).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2008 High

    Established NLRX1 as a mitochondrial negative regulator of antiviral signaling, answering whether an NLR could localize to mitochondria and tune the RIG-I/MAVS interferon axis.

    Evidence Co-IP, siRNA knockdown, IFN-β reporter and mitochondrial fractionation in cell lines

    PMID:18200010

    Open questions at the time
    • Outer-membrane localization later revised
    • Mechanism of MAVS-RIG-I disruption not structurally defined
    • Reporter-based IFN readout later questioned
  2. 2008 Medium

    Showed NLRX1 induces mitochondrial ROS and amplifies NF-κB/JNK signaling, framing it as a pro-inflammatory amplifier in contrast to its IFN-suppressive role.

    Evidence ROS assays, NF-κB/JNK reporters and co-stimulation in overexpressing cell lines

    PMID:18219313

    Open questions at the time
    • Overexpression-based
    • Molecular source of ROS not identified at this stage
    • Apparent tension with later inhibitory NF-κB findings
  3. 2009 High

    Resolved the localization controversy and provided a molecular basis for ROS generation by showing matrix import and a UQCRC2 interaction.

    Evidence Mitochondrial subfractionation, ΔΨm dependence, N-terminal sequencing and Co-IP

    PMID:19692591

    Open questions at the time
    • How matrix-localized NLRX1 reaches cytosolic immune partners unresolved
    • Functional consequence of UQCRC2 binding on ETC not quantified here
  4. 2010 Medium

    Connected NLRX1-driven ROS to a microbial outcome, showing it supports intracellular pathogen growth.

    Evidence siRNA knockdown, ROS measurement and chlamydial growth assays in epithelial cells

    PMID:20959452

    Open questions at the time
    • Single lab
    • Distinction between NADPH-oxidase and mitochondrial ROS contributions incomplete
  5. 2011 High

    Defined a MAVS-independent NF-κB inhibitory arm via a dynamic TRAF6-to-IKK partner switch, explaining how NLRX1 restrains TLR-driven inflammation in vivo.

    Evidence Nlrx1−/− mice, dynamic Co-IP, ubiquitination assay and LPS sepsis model

    PMID:21703539 PMID:21703540

    Open questions at the time
    • Ubiquitin ligase mediating LPS-induced NLRX1 modification not identified
    • Stoichiometry of TRAF6/IKK switch unresolved
  6. 2012 High

    Provided structural and biochemical grounding by solving the C-terminal LRR hexamer and demonstrating RNA binding.

    Evidence X-ray crystallography at 2.65 Å and RNA-binding assay

    PMID:22386589

    Open questions at the time
    • Full-length assembly state unknown
    • Physiological RNA ligand undefined
  7. 2012 High

    Identified the TUFM complex linking NLRX1 to autophagy alongside IFN suppression, expanding its role into mitochondrial quality control.

    Evidence Quantitative MS, endogenous Co-IP, KO cells and autophagy readouts

    PMID:22749352

    Open questions at the time
    • How a matrix protein engages cytosolic ATG machinery unclear
    • Direct vs indirect ATG5-ATG12-ATG16L1 link via TUFM
  8. 2012 Medium

    Challenged the antiviral-inhibitor model with an independent knockout showing normal responses and exposed a luciferase reporter artifact.

    Evidence Independent Nlrx1−/− BMDM/MEF infection assays and reporter artifact analysis

    PMID:22718770 PMID:23212541

    Open questions at the time
    • Source of discrepancy with original studies not fully reconciled
    • Strain/background differences not resolved
  9. 2014 High

    Showed NLRX1 protects mitochondrial integrity against a viral protein, demonstrating a context where it preserves rather than suppresses antiviral function.

    Evidence Co-IP with PB1-F2, PB1-F2-deletion virus, KO macrophages and ΔΨm assay

    PMID:24799673

    Open questions at the time
    • Interaction interface not mapped
    • Generality beyond influenza unknown
  10. 2014 Medium

    Positioned NLRX1 as a metabolically regulated arbiter of extrinsic vs intrinsic apoptosis with tumor relevance.

    Evidence Gain/loss-of-function in MEFs/transformed cells, apoptosis assays and AOM/DSS tumor models

    PMID:24867956

    Open questions at the time
    • Signaling mechanism not molecularly defined
    • Link to glucose regulation mechanistically unclear
  11. 2016 High

    Extended IFN suppression to the DNA-sensing pathway by showing NLRX1 sequesters STING from TBK1.

    Evidence Co-IP, NLRX1-deficient cells and Nlrx1−/− mice challenged with DNA stimuli/viruses

    PMID:27078069

    Open questions at the time
    • Structural basis of STING sequestration unknown
    • How matrix-resident NLRX1 accesses STING unresolved
  12. 2017 High

    Revealed opposing control of IRF3 versus IRF1 through PKR-dependent translational regulation, refining the simple inhibitor model.

    Evidence KO cells, viral infection, IRF reporters, PKR activity and translation assays

    PMID:28967880

    Open questions at the time
    • Direct vs indirect effect on PKR unresolved
    • Mechanism linking NLRX1 to translational control incomplete
  13. 2017 High

    Defined a degradative mechanism for MAVS shutdown via NOD-domain-dependent PCBP2 recruitment during HCV infection.

    Evidence Co-IP, K48-ubiquitination assay, proteasome rescue and NOD-domain mutagenesis

    PMID:28956771

    Open questions at the time
    • E3 ligase identity not established
    • Virus-specificity of degradation unclear
  14. 2017 Medium

    Showed FAF1 competitively displaces NLRX1 from MAVS, identifying a regulatory release mechanism for antiviral signaling.

    Evidence Competitive Co-IP and FAF1gt/gt mouse viral infection

    PMID:28542569

    Open questions at the time
    • Single lab
    • Quantitative binding competition not measured
  15. 2017 Medium

    Demonstrated NLRX1 IFN suppression enables herpesvirus reactivation, placing it upstream of IFNβ in a viral life-cycle context.

    Evidence siRNA depletion in iSLK/BCBL-1 cells, KSHV reactivation and TBK1-inhibitor epistasis

    PMID:28459883

    Open questions at the time
    • Single lab
    • Direct molecular target in KSHV context not identified
  16. 2018 Medium

    Linked NLRX1 to mitochondrial RNA granules and post-transcriptional regulation of ETC subunits through FASTKD5.

    Evidence Fractionation, Co-IP and mitochondrial RNA processing/ETC activity assays

    PMID:29932989

    Open questions at the time
    • Direct effect on FASTKD5 catalytic function unclear
    • Single lab
  17. 2018 Medium

    Placed SARM1 downstream of NLRX1 in matrix-associated apoptosis while distinguishing this from neuronal Wallerian degeneration.

    Evidence Co-IP, fractionation, apoptosis epistasis and neuronal degeneration assays

    PMID:30191480

    Open questions at the time
    • Single lab
    • Mechanism downstream of SARM1 in apoptosis undefined
  18. 2018 Medium

    Showed NLRX1–TUFM promotes LC3-associated phagocytosis of a fungal pathogen, broadening its autophagy-related roles.

    Evidence Co-IP, LC3 lipidation, LAPosome imaging and KO/knockdown in macrophages

    PMID:30559741

    Open questions at the time
    • Single lab
    • Generality across pathogens untested here
  19. 2018 Medium

    Identified NACHT-domain-dependent inhibition of the Beclin1–UVRAG autophagy complex restraining bacterial invasion.

    Evidence CRISPR KO, Co-IP, NACHT mutagenesis and GAS invasion/autophagy assays

    PMID:30488027

    Open questions at the time
    • Single lab
    • Reconciliation with autophagy-promoting TUFM role not addressed
  20. 2015 Medium

    Identified lipid ligands binding the C-terminal LRR with defined critical residues, suggesting NLRX1 is a druggable lipid sensor modulating NF-κB.

    Evidence Molecular docking, SPR, cNLRX1 mutagenesis, NF-κB reporter and DSS colitis

    PMID:26714018

    Open questions at the time
    • Endogenous physiological ligand unestablished
    • In vitro binding affinities of modest specificity
  21. 2020 Medium

    Implicated NLRX1 as an intermediary for HPV16 E7-driven STING turnover enabling tumor immune evasion.

    Evidence NLRX1 depletion in HPV16+ HNSCC, STING level and IFN-I/T-cell assays

    PMID:31874109

    Open questions at the time
    • E7–NLRX1–STING interaction not biochemically reconstituted
    • Mechanism of degradation unresolved
  22. 2021 Medium

    Connected NLRX1 to mitophagy initiation via the FUNDC1–NIPSNAP1/2 axis in ischemia-reperfusion injury.

    Evidence Co-IP, FUNDC1 phosphorylation assay and in vivo IR injury model

    PMID:33432610

    Open questions at the time
    • Whether NLRX1 directly regulates FUNDC1 kinase unclear
    • Single lab
  23. 2022 High

    Established a major mitophagy mechanism: mitochondrial protein import stress drives cytosolic NLRX1 to recruit RRBP1 for PINK1-independent LC3 lipidation, with in vivo muscle relevance.

    Evidence MPIS induction, KO cells, Co-IP, PINK1 KO epistasis and in vivo muscle mitophagy

    PMID:35752171

    Open questions at the time
    • How NLRX1 senses import stress molecularly unknown
    • Cytosolic vs matrix pool partitioning control unresolved
  24. 2022 Medium

    Characterized O-GlcNAcylation as a PTM controlling NLRX1 stability and IKKα interaction, tuning inflammatory output in macrophages.

    Evidence Co-IP with OGT, domain mapping, ubiquitination, CHX chase and IL-1β ELISA

    PMID:35513753

    Open questions at the time
    • Single lab
    • In vivo relevance of O-GlcNAcylation untested
  25. 2020 Medium

    Showed DJ-1/SHP-1 controls dissociation of the NLRX1–TRAF6 complex during cerebral ischemia, identifying upstream regulators of its NF-κB arm.

    Evidence Reciprocal Co-IP, DJ-1 knockdown, SHP-1 inhibition, OGD/R and MCAO/R models

    PMID:32151250

    Open questions at the time
    • Single lab
    • Direct vs indirect SHP-1 action on the complex unclear
  26. 2023 Medium

    Linked NLRX1 to mitochondrial zinc trafficking via SLC39A7, coordinating mitochondrial dynamics and restraining compensatory PINK1-PRKN mitophagy.

    Evidence Co-IP, mitochondrial Zn2+ measurement, dynamics/mitophagy markers, KO model and agonist rescue

    PMID:37876250

    Open questions at the time
    • Single lab
    • Mechanism by which Zn2+ regulates dynamics machinery incomplete
  27. 2024 Medium

    Showed an NLRX1–STING interaction promoting mitophagy-mediated LC3 lipidation and limiting cytosolic mtDNA/cGAS-STING inflammation after hypoxia-reoxygenation.

    Evidence Co-IP, LC3 lipidation, Mdivi-1 epistasis and cGAS-STING assays in renal cells

    PMID:39505095

    Open questions at the time
    • Single lab
    • Reconciliation with STING-sequestration model unaddressed
  28. 2025 Medium

    Demonstrated an inner-membrane NLRX1 requirement for calcium-induced mPTP opening, linking it to cardiac IR injury via the RISK pathway.

    Evidence Subfractionation, mPTP opening assay, CsA epistasis, KO heart IRI and phosphoproteomics

    PMID:40536683

    Open questions at the time
    • Single lab, no reconstitution
    • Molecular target within the mPTP machinery unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single mitochondrially imported protein physically accesses cytosolic immune complexes (MAVS, STING, IKK, ATG/autophagy machinery) and what governs the partitioning between matrix and cytosolic pools remains the central unresolved question.
  • No model reconciling matrix import with cytosolic immune interactions
  • Conflicting knockout phenotypes for antiviral function unresolved
  • No structure of full-length NLRX1 or its immune-partner complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1 GO:0008289 lipid binding 1
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-9612973 Autophagy 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953854 Metabolism of RNA 1
Partners
FASTKD5MAVSPCBP2RRBP1STING1TRAF6TUFMUQCRC2
Complex memberships
NLRX1-TUFM autophagy complexmitochondrial RNA granule (FASTKD5)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 NLRX1 localizes to the mitochondrial outer membrane and directly interacts with MAVS (via co-immunoprecipitation), disrupting virus-induced RIG-I–MAVS interactions and potently inhibiting RLH- and MAVS-mediated interferon-beta promoter activity; siRNA depletion of NLRX1 promotes type I IFN production and decreases viral replication. Co-immunoprecipitation, siRNA knockdown, reporter assay, mitochondrial fractionation Nature High 18200010
2008 NLRX1 localizes to mitochondria and, while failing to activate NF-κB or type I IFN pathways alone, potently induces reactive oxygen species (ROS) generation from mitochondria and synergistically amplifies TNF-α-, Shigella-, and dsRNA-induced NF-κB and JNK signaling. ROS assay, NF-κB/JNK reporter assays, overexpression in cell lines, co-stimulation experiments EMBO reports Medium 18219313
2009 NLRX1 contains a functional N-terminal leader sequence that fully translocates the protein to the mitochondrial matrix (not the outer membrane) via a mechanism requiring mitochondrial inner-membrane potential (ΔΨm); the leader sequence is cleaved, generating a mature protein lacking the first 39 amino acids. NLRX1 interacts with UQCRC2, a matrix-facing subunit of respiratory chain complex III, providing a molecular basis for its role in ROS generation. Mitochondrial subfractionation, ΔΨm dissipation assay, N-terminal sequencing, co-immunoprecipitation Journal of cell science High 19692591
2011 NLRX1 negatively regulates antiviral signaling by preventing constitutive interaction of MAVS and RIG-I; additionally, NLRX1 interacts with TRAF6 and inhibits NF-κB activation downstream of LPS/TLR independently of the MAVS–RIG-I pathway. Nlrx1−/− mice show exacerbated type I IFN and IL-6 responses to influenza infection. Nlrx1−/− mouse infection model, Co-IP (NLRX1–TRAF6), cytokine measurements, histopathology Immunity High 21703540
2011 NLRX1 interacts with TRAF6 or the IKK complex in an LPS signal-dependent manner: upon LPS stimulation NLRX1 is rapidly ubiquitinated, dissociates from TRAF6, and then binds the IKK complex, inhibiting IKKα/IKKβ phosphorylation and NF-κB activation. NLRX1 knockdown markedly enhances IKK phosphorylation and cytokine production, and increases susceptibility to LPS-induced septic shock in vivo. Co-IP (NLRX1–TRAF6 and NLRX1–IKK), ubiquitination assay, siRNA knockdown, in vivo LPS sepsis model Immunity High 21703539
2012 Crystal structure of the C-terminal fragment of human NLRX1 (residues 629–975) at 2.65 Å resolution reveals an LRRNT–LRRM–LRRCT architecture that assembles into a compact hexamer stabilized by inter-subunit LRRNT and LRRCT interactions. The fragment directly binds RNA, supporting a role in intracellular viral RNA recognition. X-ray crystallography (2.65 Å), RNA-binding assay Immunity High 22386589
2012 NLRX1 does not inhibit MAVS-dependent antiviral signaling: a newly generated Nlrx1−/− mouse strain showed normal antiviral and inflammatory responses (Sendai virus, influenza A, poly I:C), contradicting earlier reports of NLRX1 as a MAVS pathway inhibitor. Additionally, overexpression of the NLRX1 LRR domain non-specifically inhibits luciferase reporter assays post-transcriptionally, explaining some earlier positive findings. Nlrx1−/− BMDM and MEF infection assays (Sendai virus, influenza), in vivo challenge, luciferase reporter artifact analysis Innate immunity / Journal of Biological Chemistry Medium 22718770 23212541
2012 NLRX1 forms a complex with the mitochondrial protein TUFM (mitochondrial Tu translation elongation factor) as identified by quantitative mass spectrometry and confirmed by endogenous Co-IP. This NLRX1–TUFM complex inhibits RLR-induced type I IFN production and simultaneously promotes autophagy during viral infection; TUFM also interacts with ATG5–ATG12–ATG16L1 to modulate autophagic flux. Quantitative mass spectrometry, endogenous Co-IP, Nlrx1−/− cells, autophagy assays, viral infection Immunity High 22749352
2014 NLRX1 directly binds influenza A virus PB1-F2 protein in the mitochondria of macrophages (confirmed by Co-IP and gain/loss-of-function interaction studies), preventing PB1-F2-induced disruption of mitochondrial membrane potential and macrophage apoptosis, thereby preserving type I IFN signaling and macrophage antiviral function. Co-immunoprecipitation (NLRX1–PB1-F2), Nlrx1−/− macrophages, recombinant virus lacking PB1-F2, mitochondrial membrane potential assay PNAS High 24799673
2014 NLRX1 controls the balance between extrinsic and intrinsic apoptosis: in transformed fibroblasts it mediates resistance to extrinsic (TNF/TRAIL) but susceptibility to intrinsic (glycolysis inhibition, elevated Ca2+, ER stress) apoptotic signals. NLRX1 expression is glucose-regulated and suppressed by SV40 transformation. Gain/loss-of-function in MEFs and transformed cell lines, apoptosis assays (extrinsic vs. intrinsic stimuli), Nlrx1−/− mouse tumor models (azoxymethane, AOM/DSS) Journal of Biological Chemistry Medium 24867956
2016 NLRX1 sequesters STING away from its interaction with TBK1, preventing STING-dependent type I IFN induction in response to cytosolic DNA, cGAMP, c-di-GMP, HIV-1, and DNA viruses. NLRX1-deficient cells and Nlrx1−/− mice exhibit amplified STING-dependent innate immune responses to DNA stimuli and reduced viral loads. Co-IP (NLRX1–STING), NLRX1-deficient cells, Nlrx1−/− mouse viral infection (DNA viruses), STING–TBK1 interaction assay Cell host & microbe High 27078069
2017 NLRX1 exerts opposing regulatory effects on IRF3 and IRF1: it suppresses MAVS-mediated IRF3 activation while facilitating virus-induced increases in IRF1 protein abundance. NLRX1 prevents IRF1 translational shutdown by limiting dsRNA-activated PKR kinase activity, thereby allowing IRF1-dependent antiviral gene expression. Nlrx1−/− cells, viral infection, IRF1/IRF3 reporter assays, PKR activity assays, polysome/translation assays Nature immunology High 28967880
2017 During HCV infection, NLRX1 interacts with MAVS and recruits PCBP2 to induce K48-linked polyubiquitination and proteasomal degradation of MAVS, thereby attenuating RLR–MAVS antiviral signaling. Mutagenesis showed the NOD domain of NLRX1 is essential for interaction with PCBP2. Co-IP (NLRX1–MAVS–PCBP2), ubiquitination assay (K48-linkage), proteasome inhibitor rescue, site-directed mutagenesis of NOD domain, siRNA knockdown Journal of virology High 28956771
2017 FAF1 competes with MAVS for binding to NLRX1; FAF1 binding to NLRX1 displaces NLRX1 from MAVS, freeing MAVS to engage RIG-I and activate the MAVS–RIG-I antiviral signaling cascade. FAF1gt/gt mice deficient in FAF1 show low type I IFN and high susceptibility to RNA virus infection. Co-IP (FAF1–NLRX1–MAVS competitive binding), FAF1gt/gt mice, viral infection, IFN assays PLoS pathogens Medium 28542569
2018 NLRX1 resides in mitochondrial RNA granules (MRGs) and associates with FASTKD5, a bona fide MRG component. This NLRX1–FASTKD5 association negatively regulates post-transcriptional processing of mitochondria-encoded transcripts for complex I and complex IV subunits, modulating ETC complex activity and supercomplex formation. Mitochondrial fractionation, Co-IP (NLRX1–FASTKD5), mitochondrial RNA processing assays, ETC complex activity measurements Biochimica et biophysica acta. Molecular cell research Medium 29932989
2018 NLRX1 associates with SARM1 in the mitochondrial matrix of non-neuronal cells; the apoptotic function of NLRX1 is fully dependent on SARM1, placing SARM1 downstream of NLRX1 in the apoptosis regulatory pathway. In primary neurons, NLRX1 does not contribute to Wallerian degeneration, which requires the cytosolic pool of SARM1. Co-IP (NLRX1–SARM1), mitochondrial fractionation (SARM1 distribution), apoptosis assays in NLRX1/SARM1 knockdown/KO cells, Wallerian degeneration assay in neurons Molecular and cellular biochemistry Medium 30191480
2018 NLRX1 facilitates Histoplasma capsulatum-induced LC3-associated phagocytosis (LAP) in macrophages by interacting with TUFM, which in turn associates with ATG5–ATG12 to promote LAPosome formation and MAPKs–AP-1-dependent cytokine responses. Loss of either NLRX1 or TUFM reduces LAP induction. Co-IP (NLRX1–TUFM–ATG5/12), LC3 lipidation assay, LAPosome imaging, Nlrx1−/− macrophages, TUFM silencing, MAPK/cytokine assays Frontiers in immunology Medium 30559741
2020 HPV16 E7 uses NLRX1 as a critical intermediary to facilitate STING protein turnover (degradation), enabling immune evasion in head and neck squamous cell carcinoma. Depletion of NLRX1 restores STING levels, enhances IFN-I-dependent T cell infiltration, and improves tumor control. NLRX1 depletion in HPV16+ HNSCC cells, STING protein level assays, IFN-I pathway assays, T cell infiltration analysis, tissue microarrays Journal of Clinical Investigation Medium 31874109
2015 Molecular docking and surface plasmon resonance (SPR) identified punicic acid (PUA), eleostearic acid (ESA), and docosahexaenoic acid (DHA) as ligands that bind the C-terminal LRR fragment of NLRX1 (cNLRX1). Mutagenesis of residues D677, F680, F681, and E684 diminished ligand affinity. PUA and DHA suppress NF-κB activity in macrophages in an NLRX1-dependent manner. Molecular docking, SPR spectroscopy, site-directed mutagenesis of cNLRX1, NF-κB reporter assay in BMDM, DSS colitis model PLoS One Medium 26714018
2022 Mitochondrial protein import stress (MPIS) triggers PINK1-independent LC3 lipidation and mitophagy through a pathway requiring NLRX1. Under MPIS, NLRX1 is retained in the cytosol where it recruits RRBP1 (an ER transmembrane protein that relocates to mitochondrial vicinity during MPIS); the NLRX1/RRBP1 complex controls LC3 recruitment and lipidation at the mitophagosome formation site. NLRX1 also controls skeletal muscle mitophagy in vivo during exercise. MPIS induction (MG132, CCCP, heat shock), NLRX1 KO cells, Co-IP (NLRX1–RRBP1), LC3 lipidation assay, PINK1 KO epistasis, in vivo skeletal muscle mitophagy assay Molecular cell High 35752171
2021 NLRX1 regulates mitophagy via the FUNDC1–NIPSNAP1/NIPSNAP2 axis: NLRX1 loss promotes phosphorylation of FUNDC1, which prevents FUNDC1 from interacting with NIPSNAP1/2 on the outer membrane of damaged mitochondria, blocking mitophagy initiation and causing accumulation of damaged mitochondria and epithelial apoptosis in intestinal ischemia-reperfusion injury. Co-IP (FUNDC1–NIPSNAP1/2), NLRX1 overexpression in rats and IEC-6 cells, Western blotting, FUNDC1 phosphorylation assay, in vivo IR injury model Cell proliferation Medium 33432610
2023 NLRX1 forms a complex with the zinc transporter SLC39A7 on the mitochondrial membrane of nucleus pulposus cells, modulating mitochondrial Zn2+ trafficking and thereby orchestrating mitochondrial dynamics (fission/fusion via p-DNM1L, L/S-OPA1, OMA1) and mitophagy activity. Loss of NLRX1 activates compensatory PINK1-PRKN pathway leading to excessive mitophagy and cell senescence. Co-IP (NLRX1–SLC39A7), mitochondrial Zn2+ measurement, mitochondrial dynamics markers (Western blot), mitophagy assays, Nlrx1 KO animal model, NLRX1 overexpression and pharmacological agonist (NX-13) rescue Autophagy Medium 37876250
2017 NLRX1 negatively modulates type I IFN to facilitate KSHV lytic reactivation from latency. NLRX1 depletion elevates IFNβ transcription and JAK/STAT pathway gene expression, suppressing viral transcription and particle production. Blocking IFNβ production (TBK1 inhibitor or siRNA) largely abolishes the effect of NLRX1 depletion on KSHV reactivation, placing NLRX1 upstream of IFNβ in this context. NLRX1 siRNA depletion in iSLK.219 and BCBL-1 cells, KSHV lytic reactivation assay, viral particle quantification, TBK1 inhibitor (BX795) epistasis, IFNβ/JAK-STAT qPCR PLoS pathogens Medium 28459883
2018 NLRX1 negatively regulates the Beclin 1–UVRAG autophagy complex by directly interacting with Beclin 1 via its NACHT domain, inhibiting Group A Streptococcus (GAS) invasion and autophagosome/autolysosome formation. NLRX1 knockout markedly increases GAS invasion and autophagic processes, and loss of Beclin 1 or UVRAG inhibits invasion and autophagy. NLRX1 KO cells (CRISPR), Co-IP (NLRX1–Beclin 1–UVRAG), NACHT domain mutagenesis, GAS invasion assay, autophagosome/autolysosome imaging Frontiers in cellular and infection microbiology Medium 30488027
2017 DJ-1 promotes dissociation of NLRX1 from TRAF6 during cerebral ischemia-reperfusion by facilitating interaction of SHP-1 with TRAF6. DJ-1 knockdown facilitates NLRX1–TRAF6 interaction and increases inflammatory cytokine production, whereas SHP-1 inhibition recapitulates DJ-1 knockdown effects on the NLRX1–TRAF6 complex. Co-IP (NLRX1–TRAF6, SHP-1–TRAF6), DJ-1 siRNA knockdown, SHP-1 inhibitor, OGD/R in vitro astrocyte model, MCAO/R in vivo model Journal of neuroinflammation Medium 32151250
2022 NLRX1 undergoes O-GlcNAcylation via interaction with O-GlcNAc transferase (OGT) through its NBD domain; elevated O-GlcNAcylation promotes NLRX1 ubiquitination and decreases NLRX1 protein stability, while enhancing interaction between NLRX1 and IKK-α, thereby reducing IL-1β expression in M1 macrophages. Co-IP (NLRX1–OGT), domain mapping, ubiquitination assay, cycloheximide chase, O-GlcNAcylation assay, IKK-α Co-IP, IL-1β ELISA In vitro cellular & developmental biology Medium 35513753
2025 NLRX1 localizes to the inner mitochondrial membrane (by subfractionation) and is required for calcium-induced mitochondrial permeability transition pore (mPTP) opening. NLRX1 deletion completely abolishes calcium-induced mPTP opening and cyclosporine A (CsA) effects on mPTP, increases mitochondrial calcium content after IR, and impairs RISK pathway (Akt, ERK, S6K) activation; CsA treatment abolishes IRI differences between KO and WT hearts, indicating permanent mPTP closure in KO contributes to increased IR injury. Mitochondrial subfractionation, Ca2+-induced mPTP opening assay in isolated mitochondria, cyclosporine A epistasis, Nlrx1 KO isolated mouse heart IRI model, RISK pathway Western blot, Seahorse respirometry, phosphoproteomics Basic research in cardiology Medium 40536683
2024 NLRX1 directly binds STING (by Co-IP) and promotes mitophagy-mediated LC3 lipidation after hypoxia-reoxygenation injury; STING inhibition reverses NLRX1-induced mitochondrial LC3 lipidation, placing STING downstream of NLRX1 in this mitophagy axis. NLRX1 overexpression also reduces cytoplasmic mtDNA and inhibits cGAS–STING inflammatory signaling. Co-IP (NLRX1–STING), LC3 lipidation assay, Mdivi-1 mitophagy inhibitor epistasis, mtDNA cytoplasmic measurement, cGAS-STING pathway assays, NLRX1 overexpression in renal cells Experimental cell research Medium 39505095
2014 NLRX1 promotes DRP1 phosphorylation and increases mitochondrial fission; it redirects neuronal cells from necrosis toward apoptosis following rotenone-induced mitochondrial stress. Transfection of N2A cells, rotenone treatment, DRP1 phosphorylation Western blot, cell death classification assays Molecular brain Low 25540124
2010 NLRX1 is required for optimal chlamydial growth by enhancing ROS production in infected epithelial cells; siRNA depletion of NLRX1 reduces ROS levels (both NADPH oxidase-derived and mitochondrial) and impairs Chlamydia trachomatis growth. NLRX1 siRNA knockdown, ROS measurement, chlamydial growth assay in epithelial cells Journal of Biological Chemistry Medium 20959452

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 479 18200010
2011 NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways. Immunity 321 21703540
2008 NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappaB and JNK pathways by inducing reactive oxygen species production. EMBO reports 265 18219313
2012 The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity 262 22749352
2011 NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK. Immunity 248 21703539
2009 An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix. Journal of cell science 166 19692591
2020 HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING. The Journal of clinical investigation 159 31874109
2016 NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell host & microbe 140 27078069
2010 Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1. The Journal of biological chemistry 119 20959452
2014 NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein. Proceedings of the National Academy of Sciences of the United States of America 95 24799673
2017 NLRX1 dampens oxidative stress and apoptosis in tissue injury via control of mitochondrial activity. The Journal of experimental medicine 92 28626071
2021 NLRX1/FUNDC1/NIPSNAP1-2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury. Cell proliferation 84 33432610
2012 Structure and functional characterization of the RNA-binding element of the NLRX1 innate immune modulator. Immunity 79 22386589
2017 NLRX1 promotes immediate IRF1-directed antiviral responses by limiting dsRNA-activated translational inhibition mediated by PKR. Nature immunology 77 28967880
2017 NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2. Journal of virology 73 28956771
2013 The NLR protein, NLRX1, and its partner, TUFM, reduce type I interferon, and enhance autophagy. Autophagy 73 23321557
2012 NLRX1 does not inhibit MAVS-dependent antiviral signalling. Innate immunity 71 23212541
2016 NLRX1 attenuates apoptosis and inflammatory responses in myocardial ischemia by inhibiting MAVS-dependent NLRP3 inflammasome activation. Molecular immunology 66 27393910
2014 The mitochondrial protein NLRX1 controls the balance between extrinsic and intrinsic apoptosis. The Journal of biological chemistry 65 24867956
2019 NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function. Frontiers in immunology 64 31681307
2015 Suppression of NLRX1 in chronic obstructive pulmonary disease. The Journal of clinical investigation 64 25938787
2016 The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. Cell reports 60 26971998
2015 NLRX1 acts as tumor suppressor by regulating TNF-α induced apoptosis and metabolism in cancer cells. Biochimica et biophysica acta 59 25639646
2022 Mitochondrial protein import stress regulates the LC3 lipidation step of mitophagy through NLRX1 and RRBP1. Molecular cell 58 35752171
2016 EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex. Oncogene 57 26876213
2017 NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection. Microbes and infection 56 29024797
2018 NLRX1 Modulates Immunometabolic Mechanisms Controlling the Host-Gut Microbiota Interactions during Inflammatory Bowel Disease. Frontiers in immunology 55 29535731
2023 The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking. Autophagy 53 37876250
2017 Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury. Journal of immunology (Baltimore, Md. : 1950) 51 28993512
2016 NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation. Cell reports 49 26971996
2017 Insights into the diversity of NOD-like receptors: Identification and expression analysis of NLRC3, NLRC5 and NLRX1 in rainbow trout. Molecular immunology 48 28432942
2022 Type I Interferon Response Is Mediated by NLRX1-cGAS-STING Signaling in Brain Injury. Frontiers in molecular neuroscience 47 35283725
2021 Long noncoding RNA NKILA transferred by astrocyte-derived extracellular vesicles protects against neuronal injury by upregulating NLRX1 through binding to mir-195 in traumatic brain injury. Aging 46 33686956
2014 Nlrx1 regulates neuronal cell death. Molecular brain 46 25540124
2018 NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Frontiers in immunology 45 30559741
2017 NLRX1 Regulates Effector and Metabolic Functions of CD4+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 45 28159898
2020 DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke. Journal of neuroinflammation 44 32151250
2019 NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes. Cells 43 31052241
2023 A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection. Nature communications 42 36797302
2019 NLRX1 regulates TNF-α-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells. Biochimica et biophysica acta. Molecular basis of disease 42 30802640
2016 NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-κB signaling. Oncotarget 41 27105514
2019 Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease through Immunometabolic Mechanisms in CD4+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 40 31694910
2020 NLR in eXile: Emerging roles of NLRX1 in immunity and human disease. Immunology 39 33314068
2018 Activation of NLRX1-mediated autophagy accelerates the ototoxic potential of cisplatin in auditory cells. Toxicology and applied pharmacology 39 29454061
2015 Characterization of NLR-A subfamily members in miiuy croaker and comparative genomics revealed NLRX1 underwent duplication and lose in actinopterygii. Fish & shellfish immunology 37 26381931
2013 The involvement of NLRX1 and NLRP3 in the development of nonalcoholic steatohepatitis in mice. Journal of the Chinese Medical Association : JCMA 36 24084392
2020 Inhibition of microRNA-15 protects H9c2 cells against CVB3-induced myocardial injury by targeting NLRX1 to regulate the NLRP3 inflammasome. Cellular & molecular biology letters 35 32099552
2018 NLRX1 resides in mitochondrial RNA granules and regulates mitochondrial RNA processing and bioenergetic adaptation. Biochimica et biophysica acta. Molecular cell research 35 29932989
2018 The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1. Molecular and cellular biochemistry 34 30191480
2017 NLRX1 accelerates cisplatin-induced ototoxity in HEI-OC1 cells via promoting generation of ROS and activation of JNK signaling pathway. Scientific reports 33 28287190
2022 Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1. Journal of neuroinflammation 32 35414088
2017 NLRX1 negatively modulates type I IFN to facilitate KSHV reactivation from latency. PLoS pathogens 32 28459883
2019 NLRX1 alleviates lipopolysaccharide-induced apoptosis and inflammation in chondrocytes by suppressing the activation of NF-κB signaling. International immunopharmacology 30 30861394
2017 FAS-associated factor-1 positively regulates type I interferon response to RNA virus infection by targeting NLRX1. PLoS pathogens 29 28542569
2021 Focusing on the Cell Type Specific Regulatory Actions of NLRX1. International journal of molecular sciences 27 33525671
2015 Modeling the Regulatory Mechanisms by Which NLRX1 Modulates Innate Immune Responses to Helicobacter pylori Infection. PloS one 27 26367386
2019 NLRX1 of black carp suppresses MAVS-mediated antiviral signaling through its NACHT domain. Developmental and comparative immunology 26 30853538
2019 NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. PLoS biology 26 31525189
2018 Deletion of NLRX1 increases fatty acid metabolism and prevents diet-induced hepatic steatosis and metabolic syndrome. Biochimica et biophysica acta. Molecular basis of disease 26 29514047
2015 Modeling-Enabled Characterization of Novel NLRX1 Ligands. PloS one 26 26714018
2012 Post-transcriptional inhibition of luciferase reporter assays by the Nod-like receptor proteins NLRX1 and NLRC3. The Journal of biological chemistry 25 22718770
2020 LRR domain of NLRX1 protein delivery by dNP2 inhibits T cell functions and alleviates autoimmune encephalomyelitis. Theranostics 24 32194859
2019 NLRX1 Regulation Following Acute Mitochondrial Injury. Frontiers in immunology 24 31736938
2018 NLRX1 Negatively Regulates Group A Streptococcus Invasion and Autophagy Induction by Interacting With the Beclin 1-UVRAG Complex. Frontiers in cellular and infection microbiology 24 30488027
2022 The regulatory role of NLRX1 in innate immunity and human disease. Cytokine 21 36194971
2021 Macrophage-preferable delivery of the leucine-rich repeat domain of NLRX1 ameliorates lethal sepsis by regulating NF-κB and inflammasome signaling activation. Biomaterials 21 33971559
2015 Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy. AIDS (London, England) 21 26237098
2023 NLRX1: Versatile functions of a mitochondrial NLR protein that controls mitophagy. Biomedical journal 19 37574163
2020 NLRX1 is a key regulator of immune signaling during invasive pulmonary aspergillosis. PLoS pathogens 19 32956405
2018 Molecular cloning and functional characterisation of NLRX1 in grass carp (Ctenopharyngodon idella). Fish & shellfish immunology 16 30010019
2018 Male Mice Lacking NLRX1 Are Partially Protected From High-Fat Diet-Induced Hyperglycemia. Journal of the Endocrine Society 15 29577109
2018 Negative-Pressure Wound Therapy Promotes Wound Healing by Enhancing Angiogenesis Through Suppression of NLRX1 via miR-195 Upregulation. The international journal of lower extremity wounds 15 30141361
2022 Mitochondria-ER cooperation: NLRX1 detects mitochondrial protein import stress and promotes mitophagy through the ER protein RRBP1. Autophagy 14 36170592
2020 MicroRNA-195 suppresses enterovirus A71-induced pyroptosis in human neuroblastoma cells through targeting NLRX1. Virus research 14 33253716
2011 NOD so fast: NLRX1 puts the brake on inflammation. Immunity 14 21703534
2008 Innate immunity: squelching anti-viral signalling with NLRX1. Current biology : CB 14 18397740
2023 NLRX1 knockdown attenuates pro-apoptotic signaling and cell death in pulmonary hyperoxic acute injury. Scientific reports 13 36859435
2021 Black carp TUFM collaborates with NLRX1 to inhibit MAVS-mediated antiviral signaling pathway. Developmental and comparative immunology 13 34000319
2020 MiR-423-5p Regulates Cells Apoptosis and Extracellular Matrix Degradation via Nucleotide-Binding, Leucine-Rich Repeat Containing X1 (NLRX1) in Interleukin 1 beta (IL-1β)-Induced Human Nucleus Pulposus Cells. Medical science monitor : international medical journal of experimental and clinical research 13 32467560
2023 NLRX1 increases human retinal pigment epithelial autophagy and reduces H2O2-induced oxidative stress and inflammation by suppressing FUNDC1 phosphorylation and NLRP3 activation. Allergologia et immunopathologia 12 36617838
2023 NLRX1 Prevents M2 Macrophage Polarization and Excessive Renal Fibrosis in Chronic Obstructive Nephropathy. Cells 11 38201227
2012 NLRX1 has a tail to tell. Immunity 11 22444625
2017 Interactions of TRAF6 and NLRX1 gene polymorphisms with environmental factors on the susceptibility of type 2 diabetes mellitus vascular complications in a southern Han Chinese population. Journal of diabetes and its complications 9 29046236
2023 NLRX1 functions as a tumor suppressor in Pan02 pancreatic cancer cells. Frontiers in oncology 8 37342194
2021 NLRX1 can counteract innate immune response induced by an external stimulus favoring HBV infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Science progress 8 34825857
2016 The expression of NLRX1 in C57BL/6 mice cochlear hair cells: Possible relation to aging- and neomycin-induced deafness. Neuroscience letters 8 26836140
2023 NLRX1 ligand, docosahexaenoic acid, ameliorates LPS-induced inflammatory hyperalgesia by decreasing TRAF6/IKK/IkB-a/NF-kB signaling pathway activity. Cellular and molecular biology (Noisy-le-Grand, France) 7 37807339
2022 NLRX1 Deficiency Alters the Gut Microbiome and Is Further Exacerbated by Adherence to a Gluten-Free Diet. Frontiers in immunology 7 35572547
2021 NDV related exosomes enhance NDV replication through exporting NLRX1 mRNA. Veterinary microbiology 7 34274763
2021 Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific. Frontiers in immunology 7 34790195
2019 NLRX1 does not play a role in diabetes nor the development of diabetic nephropathy induced by multiple low doses of streptozotocin. PloS one 7 30908533
2025 The innate immune receptor NLRX1 is a novel required modulator for mPTP opening: implications for cardioprotection. Basic research in cardiology 6 40536683
2024 A zebrafish NLRX1 isoform downregulates fish IFN responses by targeting the adaptor STING. Journal of virology 6 38193691
2024 NLRX1 and STING alleviate renal ischemia-reperfusion injury by regulating LC3 lipidation during mitophagy. Experimental cell research 6 39505095
2022 The interaction of O-GlcNAc-modified NLRX1 and IKK-α modulates IL-1β expression in M1 macrophages. In vitro cellular & developmental biology. Animal 6 35513753
2020 Characterization and expression analysis of mitochondrial localization molecule: NOD-like receptor X1 (Nlrx1) in mucosal tissues of turbot (Scophthalmus maximus) following bacterial challenge. Developmental and comparative immunology 6 33248045
2016 NLRX1 Helps HIV Avoid a STING Operation. Cell host & microbe 6 27078064
2024 NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1. Antioxidants (Basel, Switzerland) 5 38671928
2023 Cellular Context Dictates the Suppression or Augmentation of Triple-Negative Mammary Tumor Metastasis by NLRX1. Journal of immunology (Baltimore, Md. : 1950) 5 37909827
2022 Dexmedetomidine Alleviates Hypoxic-Ischemic Brain Damage in Neonatal Rats Through Reducing MicroRNA-134-5p-Mediated NLRX1 Downregulation. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 5 35259612

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