id: Q14534
gene_symbol: SQLE
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SQLE encodes squalene monooxygenase (squalene epoxidase; EC 1.14.14.17), an FAD-dependent
  flavoprotein monooxygenase that catalyzes the stereospecific oxidation of squalene to
  (S)-2,3-epoxysqualene (2,3-oxidosqualene), consuming molecular oxygen and using reducing
  equivalents supplied by NADPH via NADPH-cytochrome P450 reductase. This is the first
  oxygenation step of sterol biosynthesis and the second rate-limiting step of the cholesterol
  biosynthetic pathway, acting downstream of HMG-CoA reductase and between squalene synthase
  (FDFT1) and lanosterol synthase (LSS). The enzyme is an endoplasmic reticulum (microsome)
  membrane protein associated peripherally with the membrane through N-terminal and C-terminal
  hydrophobic regions rather than transmembrane helices. Its N-terminal regulatory domain
  senses cholesterol and mediates cholesterol-accelerated, MARCHF6-dependent ubiquitin-
  proteasome degradation, providing feedback control of flux through the pathway. SQLE is a
  validated antifungal and anticancer drug target.
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred endoplasmic reticulum localization. SQLE is a well-established
      ER/microsome membrane enzyme, so this is correct but broader than the specific ER membrane
      location captured by the IDA/IEA annotations.
    action: ACCEPT
    reason: >-
      IBA localization consistent with all experimental evidence. ER is a correct compartment;
      the more specific and preferred CC term is endoplasmic reticulum membrane (GO:0005789),
      captured elsewhere in this record.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
    - reference_id: Reactome:R-HSA-191299
      supporting_text: "Squalene monooxygenase (squalene epoxidase, SE) is located on the endoplamic reticulum."
- term:
    id: GO:0004506
    label: squalene monooxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred squalene monooxygenase activity. This is the core, defining
      molecular function of SQLE across eukaryotes and is directly supported by human
      enzymology and crystal structures.
    action: ACCEPT
    reason: >-
      IBA correctly identifies the core catalytic function. Human recombinant enzyme was
      purified and kinetically characterized (PMID:10666321), and the catalytic domain
      structure with FAD was solved (PMID:30626872). Represents the core function of the gene.
    supported_by:
    - reference_id: PMID:30626872
      supporting_text: "SQLE is a flavin adenosine dinucleotide (FAD)–dependent epoxidase that catalyzes stereospecific conversion of non-sterol intermediate squalene to 2,3(S)-oxidosqualene"
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Catalyzes the stereospecific oxidation of squalene to"
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement in sterol biosynthesis. SQLE catalyzes the first
      oxygenation step of the sterol pathway, so this BP annotation is correct.
    action: ACCEPT
    reason: >-
      Correct and well-supported. In humans the specific downstream product pathway is
      cholesterol biosynthesis (GO:0006695); sterol biosynthetic process is the conserved,
      broader biological process appropriate for the pan-eukaryotic IBA. Core function.
    supported_by:
    - reference_id: PMID:30626872
      supporting_text: "the first oxygenation step in cholesterol synthesis"
- term:
    id: GO:0004506
    label: squalene monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of squalene monooxygenase activity (ARBA/RHEA:25282/EC:1.14.14.17).
      Matches the experimentally established core function.
    action: ACCEPT
    reason: >-
      The IEA mapping (RHEA:25282, EC 1.14.14.17) corresponds exactly to the reaction catalyzed
      by human SQLE and is corroborated by experimental evidence.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "EC=1.14.14.17"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic CC annotation from UniProt Subcellular Location mapping (SL-0097). Matches the
      experimentally determined ER membrane localization.
    action: ACCEPT
    reason: >-
      Correct and specific. SQLE is a peripheral ER/microsome membrane protein; supported by
      experimental topology work and by the IDA annotation from PMID:26434806.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the generic term membrane. Correct but far less
      informative than the specific ER membrane location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong (SQLE is membrane-associated), but membrane is an uninformative parent of the
      specific and preferred endoplasmic reticulum membrane (GO:0005789) already annotated.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to sterol biosynthetic process, matching the enzyme
      family's conserved role.
    action: ACCEPT
    reason: >-
      Correct BP for the squalene monooxygenase family; consistent with the IBA and
      experimental IDA annotations to the same term.
    supported_by:
    - reference_id: PMID:30626872
      supporting_text: "the first oxygenation step in cholesterol synthesis"
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation for FAD binding. SQLE is an FAD-dependent flavoprotein;
      FAD is a required, structurally resolved cofactor.
    action: ACCEPT
    reason: >-
      Correct cofactor-binding MF (equivalent to the IDA FAD binding annotation GO:0071949).
      FAD binding is a supporting molecular function of the catalytic activity rather than the
      core function itself.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Name=FAD; Xref=ChEBI:CHEBI:57692;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Binary-interactome (HuRI) protein-protein interactions. UniProt records the corresponding
      partners as CREB3L1 (Q96BA8), REEP4 (Q9H6H4) and TMEM14B (Q9NUH8). The bare protein
      binding term is uninformative about SQLE's function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, the generic protein binding (GO:0005515) term does not convey a
      specific molecular function. These high-throughput two-hybrid interactions (CREB3L1,
      REEP4, TMEM14B) are retained as recorded but flagged as over-annotation; they should not
      be treated as a core function.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Q14534; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-3905171, EBI-6942903;"
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (ARBA) to the broad cholesterol metabolic process. SQLE participates
      in cholesterol metabolism via its role in cholesterol biosynthesis.
    action: ACCEPT
    reason: >-
      Correct but general. The specific role is cholesterol biosynthetic process (GO:0006695),
      of which this is a parent; retained as accurate non-core context.
    supported_by:
    - reference_id: PMID:33791309
      supporting_text: "two rate-limiting enzymes, 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) and squalene monooxygenase (SQLE)"
- term:
    id: GO:1904614
    label: response to biphenyl
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic ortholog transfer (Ensembl Compara, from rat Sqle P52020) of a narrow
      "response to biphenyl" phenotype. There is no human evidence and no clear connection to
      SQLE's core enzymatic function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated ortholog-transferred response term based solely on a single rodent
      dataset; it does not represent a core or well-supported human function. Retained but
      flagged as over-annotation rather than removed, as it is an electronic ortholog inference.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: "Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IC
  original_reference_id: PMID:30626872
  qualifier: involved_in
  review:
    summary: >-
      Curator inference (from the squalene monooxygenase activity, GO:0004506) that SQLE is
      involved in cholesterol biosynthesis. This is the specific human pathway role.
    action: ACCEPT
    reason: >-
      SQLE catalyzes the first oxygenation (epoxidation) step of the cholesterol biosynthetic
      pathway; the IC from the catalytic activity is sound and represents a core biological
      process for this gene.
    supported_by:
    - reference_id: PMID:30626872
      supporting_text: "the first oxygenation step in cholesterol synthesis"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:26434806
  qualifier: is_active_in
  review:
    summary: >-
      Direct experimental determination that the sterol-responsive N-terminal domain of SQLE is
      integrally associated with the ER membrane, localizing the active enzyme to the ER membrane.
    action: ACCEPT
    reason: >-
      Topology mapping of SM N100-GFP by cysteine-accessibility placed SQLE in the ER membrane;
      the enzyme functions at this location. Core cellular location for the protein.
    supported_by:
    - reference_id: PMID:26434806
      supporting_text: "We have identified a region integrally associated with the endoplasmic reticulum \nmembrane"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:33791309
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence that SQLE controls cellular cholesterol levels: SQLE
      knockdown lowers cholesterol and SQLE overexpression raises it, and SQLE is required for
      MYC-driven cholesterol production.
    action: ACCEPT
    reason: >-
      Functional genetic manipulation (siRNA/overexpression, cholesterol quantification)
      directly implicates SQLE in cholesterol biosynthesis. Core biological process.
    supported_by:
    - reference_id: PMID:33791309
      supporting_text: "Through transcriptional upregulation of SQLE, a rate-limiting enzyme in \ncholesterol synthesis pathway, MYC increases cholesterol production and promotes \ntumor cell growth."
- term:
    id: GO:0004506
    label: squalene monooxygenase activity
  evidence_type: EXP
  original_reference_id: PMID:10666321
  qualifier: enables
  review:
    summary: >-
      Experimental enzymology: human squalene monooxygenase was cloned, expressed in E. coli,
      purified, and kinetically characterized, confirming squalene monooxygenase activity with
      FAD and NADPH-cytochrome P450 reductase as partners.
    action: ACCEPT
    reason: >-
      Gold-standard biochemical demonstration of the core catalytic activity (Km squalene
      7.7 uM, Km FAD 0.3 uM). Core molecular function.
    supported_by:
    - reference_id: PMID:10666321
      supporting_text: "The cDNA for human squalene monooxygenase, a key enzyme in the committed pathway \nfor cholesterol biosynthesis, was amplified from a human liver cDNA library and \ncloned, and the protein was expressed in Escherichia coli and purified."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29765154
  qualifier: enables
  review:
    summary: >-
      Physical interaction of SQLE with the cancer-associated microprotein CASIMO1/SMIM22
      (isoform K7EJ46). The interaction modulates SQLE protein accumulation and lipid droplet
      formation, but the bare protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Genuine, experimentally supported interaction with CASIMO1 (SMIM22), but per curation
      guidelines protein binding (GO:0005515) is too generic to be a molecular function.
      Retained as recorded and flagged; the functional consequences are captured by the
      associated lipid droplet / proliferation BP annotations.
    supported_by:
    - reference_id: PMID:29765154
      supporting_text: "CASIMO1 microprotein interacts with squalene epoxidase (SQLE), a key enzyme in \ncholesterol synthesis and a known oncogene in breast cancer."
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "SMIM22; this interaction modulates lipid droplet formation"
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:29765154
  qualifier: involved_in
  review:
    summary: >-
      SQLE knockdown mimics the CASIMO1 knockdown proliferation phenotype and SQLE
      overexpression rescues it, implicating SQLE in the control of cell proliferation in breast
      cancer cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported but a downstream, cell-context (cancer) consequence of altered
      cholesterol/lipid metabolism rather than the core molecular function of the enzyme. Keep
      as a valid non-core process annotation.
    supported_by:
    - reference_id: PMID:29765154
      supporting_text: "SQLE \nknockdown mimicked the CASIMO1 knockdown phenotype and in turn SQLE \noverexpression fully rescued the effect of CASIMO1 knockdown."
- term:
    id: GO:0140042
    label: lipid droplet formation
  evidence_type: IMP
  original_reference_id: PMID:29765154
  qualifier: involved_in
  review:
    summary: >-
      Modulation of CASIMO1 (which interacts with SQLE) alters lipid droplet clustering, and the
      SQLE-CASIMO1 interaction is reported to modulate lipid droplet formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the CASIMO1/SQLE study, but a peripheral, context-specific role linked to
      the interaction with SMIM22 rather than the core sterol-biosynthetic enzyme activity.
      Retain as non-core.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "SMIM22; this interaction modulates lipid droplet formation"
    - reference_id: PMID:29765154
      supporting_text: "increased lipid droplet clustering"
- term:
    id: GO:0004506
    label: squalene monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:30626872
  qualifier: enables
  review:
    summary: >-
      Direct assay of squalene monooxygenase activity across recombinant catalytic domain,
      full-length baculosome, and human liver microsome systems, with FAD/squalene kinetics and
      an LC-MS 2,3-oxidosqualene product assay.
    action: ACCEPT
    reason: >-
      High-quality direct biochemical demonstration of the core catalytic function alongside
      crystal structures. Core molecular function.
    supported_by:
    - reference_id: PMID:30626872
      supporting_text: "SQLE is a flavin adenosine dinucleotide (FAD)–dependent epoxidase that catalyzes stereospecific conversion of non-sterol intermediate squalene to 2,3(S)-oxidosqualene"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:30626872
  qualifier: located_in
  review:
    summary: >-
      Membrane association observed for SQLE, consistent with its C-terminal hydrophobic
      membrane-binding helices. Generic membrane term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct but uninformative; the specific location is the endoplasmic reticulum membrane
      (GO:0005789), and SQLE is a peripheral membrane protein without transmembrane helices.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "mediate interaction with membranes"
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:30626872
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence linking SQLE catalytic activity to sterol (cholesterol) biosynthesis via
      production of 2,3-oxidosqualene, the first oxygenation intermediate.
    action: ACCEPT
    reason: >-
      Well-supported core BP; the enzyme's catalytic step is committed to sterol/cholesterol
      biosynthesis.
    supported_by:
    - reference_id: PMID:30626872
      supporting_text: "the first oxygenation step in cholesterol synthesis"
- term:
    id: GO:0043231
    label: intracellular membrane-bounded organelle
  evidence_type: IDA
  original_reference_id: PMID:30626872
  qualifier: located_in
  review:
    summary: >-
      Generic organelle localization consistent with ER (a membrane-bounded organelle)
      localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct but very general parent of the specific endoplasmic reticulum membrane location;
      uninformative as an independent annotation.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0071949
    label: FAD binding
  evidence_type: IDA
  original_reference_id: PMID:30626872
  qualifier: enables
  review:
    summary: >-
      Crystal structures of the SQLE catalytic domain were solved in complex with FAD, with
      multiple defined FAD-binding residues, directly demonstrating FAD binding.
    action: ACCEPT
    reason: >-
      Direct structural evidence of the FAD cofactor and its binding pocket. FAD binding is a
      supporting molecular function enabling the core squalene monooxygenase catalysis.
    supported_by:
    - reference_id: file:human/SQLE/SQLE-uniprot.txt
      supporting_text: "X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 118-574 IN COMPLEXES WITH FAD AND"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655844
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement placing SQLE at the ER membrane (Expression of
      Squalene Monooxygenase module). Consistent with all other evidence.
    action: ACCEPT
    reason: >-
      Correct and specific ER membrane localization, corroborated by IDA and IEA annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-191299
      supporting_text: "Squalene monooxygenase (squalene epoxidase, SE) is located on the endoplamic reticulum."
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191299
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for the reaction "Squalene is oxidized to its epoxide", placing squalene
      monooxygenase at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct ER membrane localization tied to the catalytic reaction module; consistent with
      experimental evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-191299
      supporting_text: "It catalyzes the oxidation of squalene (SQNE) to squalene 2,3-epoxide (SQNX)"
- term:
    id: GO:0004506
    label: squalene monooxygenase activity
  evidence_type: NAS
  original_reference_id: PMID:9286711
  qualifier: enables
  review:
    summary: >-
      Non-traceable author statement (gene-mapping paper) asserting the squalene epoxidase
      function. The catalytic function is independently confirmed experimentally.
    action: ACCEPT
    reason: >-
      Although only NAS in this reference, the core squalene monooxygenase activity is firmly
      established by EXP/IDA evidence (PMID:10666321, PMID:30626872). Accept as consistent.
    supported_by:
    - reference_id: PMID:9286711
      supporting_text: "Squalene epoxidase (EC 1.14.99.7) catalyzes the first oxygenation step in sterol \nbiosynthesis"
- term:
    id: GO:0016126
    label: sterol biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:9286711
  qualifier: involved_in
  review:
    summary: >-
      Non-traceable author statement that squalene epoxidase acts in sterol biosynthesis. This
      is correct and supported by experimental evidence elsewhere.
    action: ACCEPT
    reason: >-
      Consistent with the established role of SQLE in sterol/cholesterol biosynthesis; corroborated
      by IBA and experimental IDA annotations.
    supported_by:
    - reference_id: PMID:9286711
      supporting_text: "catalyzes the first oxygenation step in sterol \nbiosynthesis and is suggested to be one of the rate-limiting enzymes in this \npathway"
core_functions:
- description: >-
    FAD-dependent squalene monooxygenase (squalene epoxidase) activity: stereospecific
    epoxidation of squalene with molecular oxygen and NADPH-derived reducing equivalents to
    yield (S)-2,3-epoxysqualene, the first oxygenation step of sterol/cholesterol biosynthesis,
    at the endoplasmic reticulum membrane.
  molecular_function:
    id: GO:0004506
    label: squalene monooxygenase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  - id: GO:0016126
    label: sterol biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:30626872
    supporting_text: "SQLE is a flavin adenosine dinucleotide (FAD)–dependent epoxidase that catalyzes stereospecific conversion of non-sterol intermediate squalene to 2,3(S)-oxidosqualene"
  - reference_id: PMID:10666321
    supporting_text: "The cDNA for human squalene monooxygenase, a key enzyme in the committed pathway \nfor cholesterol biosynthesis, was amplified from a human liver cDNA library and \ncloned, and the protein was expressed in Escherichia coli and purified."
  - reference_id: file:human/SQLE/SQLE-uniprot.txt
    supporting_text: "Endoplasmic reticulum membrane"
- description: >-
    FAD cofactor binding that enables the flavoprotein monooxygenase catalysis; a required
    supporting molecular function of the squalene monooxygenase activity.
  molecular_function:
    id: GO:0071949
    label: FAD binding
  supported_by:
  - reference_id: file:human/SQLE/SQLE-uniprot.txt
    supporting_text: "Name=FAD; Xref=ChEBI:CHEBI:57692;"
  - reference_id: PMID:30626872
    supporting_text: "SQLE is a flavin adenosine dinucleotide (FAD)–dependent epoxidase"
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond MARCHF6-mediated cholesterol-dependent degradation, what other post-translational
    inputs (e.g. unsaturated fatty acids, ERAD partners) tune SQLE stability in vivo?
- question: >-
    Is the SQLE-CASIMO1 (SMIM22) interaction relevant to normal (non-cancer) lipid droplet
    biology, or is it specific to tumor cell contexts?
suggested_experiments:
- description: >-
    Reconstitute human SQLE with NADPH-cytochrome P450 reductase and measure epoxidation of
    squalene to (S)-2,3-epoxysqualene to formally confirm the physiological electron-donor
    coupling and stoichiometry.
  experiment_type: in vitro enzymatic reconstitution
- description: >-
    Structure-guided mutagenesis of the N-terminal cholesterol-sensing degron (residues 62-73)
    combined with degradation assays to map the cholesterol-responsive turnover mechanism.
  experiment_type: mutagenesis and protein degradation assay
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10666321
  title: Cloning, heterologous expression, and enzymological characterization of human
    squalene monooxygenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Cloning, expression, purification and kinetics of human SQLE; establishes
      the core squalene monooxygenase activity with FAD and NADPH-cytochrome P450 reductase.
- id: PMID:26434806
  title: The Regulatory Domain of Squalene Monooxygenase Contains a Re-entrant Loop
    and Senses Cholesterol via a Conformational Change.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Maps SQLE N-terminal topology to the ER membrane and shows
      cholesterol-induced conformational change driving proteasomal degradation.
- id: PMID:29765154
  title: The cancer-associated microprotein CASIMO1 controls cell proliferation and
    interacts with squalene epoxidase modulating lipid droplet formation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes SQLE-CASIMO1 (SMIM22) interaction and its effects on lipid
      droplet formation and proliferation; supports the non-core proliferation/lipid-droplet
      annotations.
- id: PMID:30626872
  title: Structure and inhibition mechanism of the catalytic domain of human squalene
    epoxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; full text available. Crystal structures (PDB 6C6N/6C6P/6C6R) with FAD,
      kinetics, and mechanism; the definitive structural/biochemical reference for the core
      catalytic function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (HuRI). Source of high-throughput binary protein-binding interactions
      (CREB3L1, REEP4, TMEM14B); interactions are recorded in UniProt but yield only the generic
      protein binding term.
- id: PMID:33791309
  title: MYC Enhances Cholesterol Biosynthesis and Supports Cell Proliferation Through
    SQLE.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; full text available. Shows SQLE is required for MYC-driven cholesterol
      biosynthesis (knockdown/overexpression, cholesterol quantification); supports the
      cholesterol biosynthetic process IDA.
- id: PMID:9286711
  title: Localization of the squalene epoxidase gene (SQLE) to human chromosome region
    8q24.1.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Chromosomal mapping paper (8q24.1); asserts the squalene epoxidase
      function only as an NAS-level statement.
- id: Reactome:R-HSA-1655844
  title: Expression of Squalene Monooxygenase (SQLE)
  findings: []
- id: Reactome:R-HSA-191299
  title: Squalene is oxidized to its epoxide
  findings: []
- id: file:human/SQLE/SQLE-uniprot.txt
  title: UniProt entry Q14534 (ERG1_HUMAN), Squalene monooxygenase
  findings: []