id: Q86UT6
gene_symbol: NLRX1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NLRX1 (NLR family member X1; also known as NOD5/NOD9 and CLR11.3) is an atypical
  nucleotide-binding-domain and leucine-rich-repeat-containing (NOD-like) receptor that,
  unusually for an NLR, localizes to the mitochondrion. An N-terminal mitochondrial
  transit peptide targets it to the mitochondrial outer membrane, it has a central NACHT
  NTPase domain, and a C-terminal leucine-rich-repeat region that carries an RNA-binding
  element; the protein assembles into a homohexamer. NLRX1 functions as a mitochondrial
  regulator at the intersection of antiviral innate immunity, autophagy, reactive oxygen
  species and inflammasome control. Its best-characterized role is as a negative regulator
  of MAVS-mediated (RIG-I-like helicase) antiviral signaling: by interacting with MAVS at
  the mitochondrial outer membrane it disrupts the virus-induced RIG-I-MAVS interaction and
  dampens type I interferon production, so that its depletion enhances antiviral interferon
  responses and reduces viral replication. NLRX1 also promotes autophagy by binding the
  mitochondrial elongation factor TUFM, which recruits the autophagy machinery (ATG5-ATG12,
  ATG16L1), linking it to autophagy/mitophagy and to modulation of type I interferon. It
  additionally restrains MAVS-dependent NLRP3 inflammasome activation, limiting IL-1beta/
  IL-18 production and apoptosis, and it modulates reactive oxygen species production with
  downstream effects on NF-kappaB and JNK signaling. Through these activities NLRX1 acts as
  a mitochondrial checkpoint that tunes the strength of antiviral, inflammatory and autophagic
  responses.
alternative_products:
- name: '1'
  id: Q86UT6-1
- name: '2'
  id: Q86UT6-2
  sequence_note: VSP_027158, VSP_027159
existing_annotations:
- term:
    id: GO:0039536
    label: negative regulation of RIG-I signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment of negative regulation of RIG-I signaling, strongly corroborated by experimental evidence that NLRX1 disrupts the virus-induced RIG-I-like-helicase-MAVS interaction and dampens type I IFN. Core function. Recent review-level synthesis (falcon) frames this as the founding NLRX1 function but cautions the effect is context-/cell-type-dependent rather than universally inhibitory.
    action: ACCEPT
    reason: Core biological process; NLRX1 negatively regulates the RIG-I/MAVS antiviral pathway (experimentally supported by PMID:18200010). The direction (negative regulation) is consistent across the foundational experimental papers and recent reviews, though the magnitude is reported to depend on cell type and pathogen.
    supported_by:
    - reference_id: PMID:18200010
      supporting_text: disruption of virus-induced RLH-MAVS interactions
    - reference_id: file:human/NLRX1/NLRX1-deep-research-falcon.md
      supporting_text: NLRX1 sequesters MAVS and prevents RIG-I/MAVS association, thereby reducing type I interferon and NF-κB responses to RNA viruses
    - reference_id: file:human/NLRX1/NLRX1-deep-research-falcon.md
      supporting_text: function appears context dependent rather than universally inhibitory
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) assignment of mitochondrial localization, the defining and experimentally established compartment for NLRX1 (mitochondrial outer membrane via its N-terminal transit peptide). The general "mitochondrion" term is appropriately robust to the ongoing debate over sub-compartment - recent review-level synthesis (falcon) additionally places NLRX1 in the matrix and inner mitochondrial membrane, though these sub-compartmental claims rest on uncached recent work and are not independently verified here.
    action: ACCEPT
    reason: Core localization; NLRX1 is a mitochondrial NLR. The broad mitochondrion term is well supported regardless of which mitochondrial sub-compartment dominates.
    supported_by:
    - reference_id: PMID:18200010
      supporting_text: localizes to the mitochondrial outer membrane and interacts with MAVS
    - reference_id: file:human/NLRX1/NLRX1-deep-research-falcon.md
      supporting_text: NLRX1 is the only NLR family member to localize to mitochondria
- term:
    id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment of negative regulation of canonical NF-kappaB, transferred from the mouse ortholog. This direction is genuinely contested - UniProt and the human primary paper PMID:18219313 state NLRX1 has NO inhibitory function on NF-kappaB and instead ENHANCES NF-kappaB and JNK signaling via ROS production, whereas other studies (and recent review-level synthesis captured in falcon) report a negative regulatory role acting through TRAF6/IKK. The literature is unresolved.
    action: MARK_AS_OVER_ANNOTATED
    reason: The NF-kappaB role of NLRX1 is genuinely disputed in the literature. The human-specific primary study (PMID:18219313) reports NLRX1 amplifies (not inhibits) NF-kappaB via ROS, while review-level sources continue to describe NLRX1 as a negative regulator of NF-kappaB (e.g. via TRAF6 and IKK). Because the direction is unresolved for human NLRX1, this unverified phylogenetic (IBA) inference of a strictly negative role is best treated as an over-annotation rather than accepted at face value or removed outright; the mouse-ortholog/review evidence underlying the IBA is real.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: Has no inhibitory function on NF-kappa-B signaling pathway, but enhances NF-kappa-B and JUN N-terminal kinase dependent signaling through the production of reactive oxygen species
    - reference_id: file:human/NLRX1/NLRX1-deep-research-falcon.md
      supporting_text: NLRX1 negatively regulates NF-κB activation through multiple mechanisms, including binding to TRAF6 (tumor necrosis factor receptor-associated factor 6) to prevent downstream TLR signaling, and interacting with IKK (IκB kinase) to prevent IκB phosphorylation
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of mitochondrial outer membrane localization from the UniProt subcellular location, redundant with the experimental EXP/TAS annotations. Core localization.
    action: ACCEPT
    reason: Core localization; NLRX1 resides at the mitochondrial outer membrane.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  qualifier: enables
  review:
    summary: IPI interaction (SARM1, a xeno/mouse partner) from a dynamic innate-immunity interaction network. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput innate-immunity interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: 'Q86UT6; Q6PDS3: Sarm1; Xeno; NbExp=2; IntAct=EBI-3893071, EBI-6117196'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28611246
  qualifier: enables
  review:
    summary: IPI interaction with TUFM (P49411) from a study of TUFM as a host restriction factor against avian influenza correlated with autophagy. The NLRX1-TUFM interaction is functionally central (it recruits ATG5-ATG12 to drive autophagy), but bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important NLRX1-TUFM interaction that underpins NLRX1's autophagy-promoting role, but bare protein binding is uninformative; the autophagy function is the informative annotation.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: 'Q86UT6; P49411: TUFM; NbExp=2; IntAct=EBI-3893071, EBI-359097'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localization to the mitochondrion, consistent with NLRX1's established mitochondrial localization. Core compartment.
    action: ACCEPT
    reason: Core localization; NLRX1 is a mitochondrial NLR.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane'
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:18200010
  qualifier: located_in
  review:
    summary: Experimental evidence that NLRX1 localizes to the mitochondrial outer membrane, where it interacts with MAVS. Core localization establishing the basis of its MAVS regulation.
    action: ACCEPT
    reason: Core localization with direct experimental support; the mitochondrial outer membrane is where NLRX1 engages MAVS.
    supported_by:
    - reference_id: PMID:18200010
      supporting_text: localizes to the mitochondrial outer membrane and interacts with MAVS
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:27393910
  qualifier: located_in
  review:
    summary: Experimental evidence (myocardial ischemia study) that NLRX1 localizes to mitochondria, where it regulates MAVS-dependent NLRP3 inflammasome activation. Core localization.
    action: ACCEPT
    reason: Core localization with experimental support.
    supported_by:
    - reference_id: PMID:27393910
      supporting_text: NLRX1, located in mitochondria
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomic evidence (human mitochondrial proteome) placing NLRX1 in the mitochondrion, consistent with all other evidence. Core compartment.
    action: ACCEPT
    reason: Core localization; corroborates the experimental mitochondrial localization.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9749471
  qualifier: located_in
  review:
    summary: Reactome pathway-step curation (NLRX1 binds CHUK:IKBKB:IKBKG) placing NLRX1 in the cytosol. NLRX1's dominant, experimentally established localization is the mitochondrial outer membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from a single Reactome pathway model of an IKK interaction; conflicts with the strongly supported mitochondrial outer membrane localization and is not the core compartment for NLRX1.
    supported_by:
    - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane'
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-936564
  qualifier: located_in
  review:
    summary: Reactome curation (NLRX1 inhibits MAVS-DDX58 interaction) placing NLRX1 at the mitochondrial outer membrane, consistent with the experimental localization and its MAVS-regulatory function. Core localization.
    action: ACCEPT
    reason: Core localization; matches the experimental mitochondrial outer membrane evidence and the MAVS-regulation function.
    supported_by:
    - reference_id: PMID:18200010
      supporting_text: localizes to the mitochondrial outer membrane and interacts with MAVS
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:18200010
  title: NLRX1 is a regulator of mitochondrial antiviral immunity.
  findings:
  - statement: NLRX1 localizes to the mitochondrial outer membrane and interacts with MAVS; it potently inhibits RIG-I-like-helicase- and MAVS-mediated IFN-beta promoter activity and disrupts virus-induced RLH-MAVS interactions, and its depletion enhances virus-induced type I IFN and reduces viral replication.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study establishing NLRX1 as a mitochondrial outer-membrane negative regulator of MAVS/RIG-I antiviral signaling. Basis of the core localization and RIG-I negative-regulation annotations.
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating
    type I interferon production.
  findings: []
- id: PMID:27393910
  title: NLRX1 attenuates apoptosis and inflammatory responses in myocardial ischemia
    by inhibiting MAVS-dependent NLRP3 inflammasome activation.
  findings:
  - statement: NLRX1 localizes to mitochondria and inhibits MAVS-dependent NLRP3 inflammasome activation, reducing IL-1beta/IL-18/IL-6, caspase-1 and apoptosis in hypoxia/myocardial-ischemia models.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes NLRX1's mitochondrial localization and its restraint of MAVS-dependent NLRP3 inflammasome activation / apoptosis.
- id: PMID:28611246
  title: Inhibition of Avian Influenza A Virus Replication in Human Cells by Host
    Restriction Factor TUFM Is Correlated with Autophagy.
  findings:
  - statement: TUFM acts as a host restriction factor against avian influenza in a manner correlated with autophagy; NLRX1 is the IntAct partner for the curated NLRX1-TUFM interaction underlying NLRX1's autophagy-promoting function.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the NLRX1-TUFM protein-binding annotation; the TUFM interaction is the mechanistic link to NLRX1's autophagy role (TUFM recruits ATG5-ATG12).
- id: PMID:22749352
  title: The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type
    I interferon and autophagy.
  findings:
  - statement: NLRX1 interacts with the mitochondrial elongation factor TUFM, which recruits the autophagy proteins ATG5-ATG12 (and ATG16L1); the NLRX1-TUFM complex promotes autophagy and dampens type I interferon, linking NLRX1 to autophagy/mitophagy.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Not in the GOA annotation set or cache, but cited in UniProt FUNCTION; primary source for NLRX1's TUFM-dependent autophagy-promoting role. Title/finding from PubMed metadata; full text not in cache.
- id: PMID:18219313
  title: NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappaB and JNK
    pathways by inducing reactive oxygen species production.
  findings:
  - statement: NLRX1 is a mitochondrial NLR that amplifies NF-kappaB and JNK signaling by inducing reactive oxygen species production (i.e. it does not inhibit NF-kappaB in this study).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cited in UniProt FUNCTION. Source of the human-specific view that NLRX1 enhances (rather than inhibits) NF-kappaB/JNK via ROS, which conflicts with the IBA negative-NF-kappaB annotation. Full text not in cache.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: Reactome:R-HSA-936564
  title: NLRX1 inhibits MAVS-DDX58 interaction
  findings: []
- id: Reactome:R-HSA-9749471
  title: NLRX1 binds CHUK:IKBKB:IKBKG
  findings: []
- id: file:human/NLRX1/NLRX1-deep-research-falcon.md
  title: Falcon deep research report for NLRX1
  findings:
  - statement: LLM-synthesized review of NLRX1 emphasizing an emerging "unifying" mitophagy-receptor model (direct LC3 binding, acetyl-CoA metabolite sensing), multi-compartment mitochondrial localization (matrix, inner membrane, outer membrane), and negative regulation of RIG-I/MAVS, cGAS-STING and NF-kappaB, while explicitly noting context-/cell-type-dependence of the antiviral effects.
    reference_section_type: OTHER
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: >-
      LLM synthesis (Edison/Falcon) built almost entirely from recent secondary reviews
      (Bi 2024, Pickering 2021, Chou 2023/2022, Jewell 2024) and very recent primary papers
      (Xiao 2025 mPTP; Zhang 2026 acetyl-CoA; Song 2024 SLC39A7) that are NOT in the local
      publications cache, so the cited claims could not be verified against primary text and
      are marked UNVERIFIED. Several claims are debated or go beyond what the cached primary
      literature shows: (1) Localization - falcon asserts NLRX1 is in the matrix and inner
      mitochondrial membrane in addition to the outer membrane, whereas the foundational
      cached papers (PMID:18200010, PMID:22749352) place its MAVS-regulatory activity at the
      mitochondrial outer membrane; the matrix/inner-membrane and mPTP claims rest on
      uncached 2024-2025 work. (2) Mitophagy - falcon frames direct NLRX1-LC3 binding and
      mitophagy as the overarching function, but the cached full-text PMID:22749352 states
      mitophagy "was not occurring under these test conditions" and that NLRX1 promotes
      (non-selective) autophagy indirectly via TUFM/ATG5-ATG12, not by direct LC3 binding;
      the LC3-receptor/acetyl-CoA model is newer and not independently verified here.
      (3) NF-kappaB - falcon (citing reviews) reports NLRX1 NEGATIVELY regulates NF-kappaB,
      which contradicts the human-specific cached primary report (PMID:18219313) that NLRX1
      AMPLIFIES NF-kappaB/JNK via ROS; this confirms the field is genuinely mixed. Useful as a
      pointer to recent literature and to flag controversy, but not used as sole support for
      any annotation action change.
core_functions:
- description: Acts as a mitochondrial outer-membrane negative regulator of MAVS-mediated
    (RIG-I-like helicase) antiviral signaling - interacting with MAVS to disrupt the
    virus-induced RIG-I-MAVS interaction and dampen type I interferon production.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:18200010
    supporting_text: disruption of virus-induced RLH-MAVS interactions
  directly_involved_in:
  - id: GO:0039536
    label: negative regulation of RIG-I signaling pathway
- description: Promotes autophagy by binding the mitochondrial elongation factor TUFM,
    which recruits the autophagy machinery (ATG5-ATG12, ATG16L1); this couples NLRX1 to
    autophagy and to modulation of type I interferon. Recent reviews additionally propose
    NLRX1 acts as a mitophagy receptor that directly engages LC3, but the cached primary
    full text (PMID:22749352) reports indirect, TUFM-mediated autophagy and did not observe
    mitophagy under its conditions, so the direct-LC3 mitophagy-receptor model remains an
    emerging, not yet locally verified, refinement.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:22749352
    supporting_text: The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy
  - reference_id: PMID:22749352
    supporting_text: 'autophagy of mitochondria (mitophagy) was not occurring under these test conditions'
  - reference_id: file:human/NLRX1/NLRX1-deep-research-falcon.md
    supporting_text: mitophagy regulation may represent the overarching unifying function of NLRX1
  directly_involved_in:
  - id: GO:0010508
    label: positive regulation of autophagy
- description: Restrains MAVS-dependent NLRP3 inflammasome activation, limiting IL-1beta/
    IL-18 production and apoptosis, and modulates reactive oxygen species production with
    downstream effects on NF-kappaB and JNK signaling.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:27393910
    supporting_text: regulated MAVS-dependent NLRP3 inflammasome activation
proposed_new_terms:
- proposed_name: positive regulation of autophagy
  proposed_definition: Any process that activates or increases the frequency, rate or
    extent of autophagy.
  justification: NLRX1's TUFM-dependent recruitment of ATG5-ATG12 to promote autophagy
    (PMID:22749352) is documented in UniProt FUNCTION but is not represented in the current
    GOA. A positive regulation of autophagy (GO:0010508) annotation - and potentially a
    regulation-of-mitophagy annotation - would capture this established core function.
  proposed_parent:
    id: GO:0010508
    label: positive regulation of autophagy
  supported_by:
  - reference_id: PMID:22749352
    supporting_text: The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy
  - reference_id: file:human/NLRX1/NLRX1-uniprot.txt
    supporting_text: promotes autophagy by interacting with TUFM and subsequently recruiting the autophagy-related proteins ATG5 and ATG12
suggested_questions:
- question: Is the negative-regulation-of-NF-kappaB role assigned by phylogenetic inference
    (IBA, from the mouse ortholog) correct for human NLRX1, given that human studies report
    NLRX1 amplifies NF-kappaB/JNK via ROS rather than inhibiting it?
- question: How does NLRX1 partition between its MAVS-inhibitory (antiviral-dampening) role
    and its TUFM-dependent autophagy-promoting role - are these mutually exclusive complexes,
    and how are they triggered during infection?
- question: Does human NLRX1 act as a direct mitophagy receptor via LC3 binding (as proposed
    in recent reviews and an acetyl-CoA-sensing model), or is its autophagy role indirect via
    the TUFM/ATG5-ATG12 axis as shown in the foundational study (PMID:22749352), which did not
    detect mitophagy under its conditions?
suggested_experiments:
- description: Define the endogenous NLRX1 mitochondrial interactome (MAVS versus TUFM/ATG5-ATG12)
    under resting versus viral-infection conditions by proximity labeling to test whether the
    MAVS-inhibitory and autophagy-promoting complexes are temporally or spatially separated.
- description: Test the human NF-kappaB direction directly with NLRX1 knockout/reconstitution
    plus ROS scavengers and NF-kappaB/JNK reporters to resolve whether human NLRX1 enhances
    or inhibits canonical NF-kappaB, adjudicating the disputed IBA annotation.