LSS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000250 lanosterol synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assertion of the core catalytic activity of LSS, the cyclization of (S)-2,3-oxidosqualene to lanosterol. This is the defining molecular function of the gene, extensively supported by direct experiment in human and by cross-species conservation. Reason: Correct and specific. The IBA call agrees with human experimental evidence (EXP PMID:14766201, IMP PMID:26200341, IGI PMID:7639730) and with the UniProt catalytic activity annotation (RHEA:14621, EC 5.4.99.7). Supporting Evidence: PMID:7639730 Lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7] catalyzes the cyclization of (S)-2,3-oxidosqualene to lanosterol in the reaction that forms the sterol nucleus.
GO:0006695 cholesterol biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of LSS to cholesterol biosynthesis. LSS produces lanosterol, the first cyclic sterol and the committed precursor of cholesterol, so involvement in cholesterol biosynthesis is a core biological-process role. Reason: Well supported. Human experimental evidence links LSS to cholesterol biosynthesis (IMP PMID:17186944), and UniProt describes it as the "Key enzyme in the cholesterol biosynthesis pathway". Supporting Evidence: file:human/LSS/LSS-uniprot.txt Key enzyme in the cholesterol biosynthesis pathway
GO:0005811 lipid droplet	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (IBA) assignment of LSS activity to lipid droplets, supported by proteomic co-fractionation of LSS with the lipid-droplet fraction across species. Reason: Lipid droplets are contiguous with the endoplasmic reticulum, and many ER lipid enzymes co-purify with the LD fraction (PMID:14741744, PMID:21498505). LSS may transiently associate with LDs, but its principal, experimentally established site of action is the ER membrane. Retain as a non-core localization rather than the primary functional compartment. Supporting Evidence: PMID:14741744 a fraction enriched with lipid droplets was isolated from a human hepatocyte cell line HuH7 using sucrose density gradient centrifugation
GO:0000250 lanosterol synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (IEA) assignment of lanosterol synthase activity from ARBA / RHEA:14621 / EC 5.4.99.7. Redundant with the experimentally supported core molecular function. Reason: The electronic mapping (EC 5.4.99.7 to GO:0000250) is exactly correct and matches the UniProt catalytic activity annotation and direct experimental evidence. Supporting Evidence: PMID:14766201 The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC) catalyzes the formation of lanosterol the first sterol precursor of cholesterol in mammals.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Automated (IEA) ER-membrane localization derived from UniProt subcellular-location mapping. Matches the experimentally established location of LSS. Reason: Correct and directly corroborated by experiment (EXP PMID:14766201, EXP PMID:15525992, IDA PMID:30401459). UniProt records "Endoplasmic reticulum membrane". Supporting Evidence: file:human/LSS/LSS-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005811 lipid droplet	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Automated (IEA, InterPro IPR018333 squalene cyclase) lipid-droplet localization. Duplicates the IBA and IDA lipid-droplet calls. Reason: Consistent with proteomic lipid-droplet detection of LSS, but the lipid droplet is a secondary compartment; the core, experimentally established location is the ER membrane. Keep as non-core. Supporting Evidence: PMID:21498505 both enzymes additionally localize to lipid droplets (LDs), which consist of a core of neutral lipids surrounded by a monolayer of phospholipid
GO:0006695 cholesterol biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: Automated (ARBA) assignment to cholesterol biosynthetic process. Duplicates the IBA and TAS cholesterol-biosynthesis calls. Reason: Correct. LSS produces lanosterol, the committed precursor of cholesterol; this is a core biological-process role supported by human experiment (IMP PMID:17186944). Supporting Evidence: file:human/LSS/LSS-uniprot.txt Key enzyme in the cholesterol biosynthesis pathway
GO:0016104 triterpenoid biosynthetic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Automated (IEA, InterPro IPR018333) assignment to triterpenoid biosynthetic process, reflecting the broad squalene/oxidosqualene cyclase family mapping. Reason: Not wrong at the family level: lanosterol is a triterpenoid and oxidosqualene cyclases generically make triterpenoids. In humans, however, the biologically meaningful process is the specific cholesterol/sterol biosynthetic pathway (GO:0006695), of which this term is a broader relative. Retain as non-core rather than as the primary process. Supporting Evidence: PMID:15525992 In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene.
GO:0016866 intramolecular transferase activity	IEA GO_REF:0000002	MODIFY	Summary: Automated (IEA, InterPro) assignment of the parent activity "intramolecular transferase activity". Lanosterol synthase activity (GO:0000250) is a descendant of this term. Reason: Correct branch but far too general. The precise, experimentally established molecular function is lanosterol synthase activity (GO:0000250), a specific child of the intramolecular oxidosqualene/lanosterol cyclase lineage. Replace with the specific term. Proposed replacements: lanosterol synthase activity Supporting Evidence: PMID:7639730 Lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7] catalyzes the cyclization of (S)-2,3-oxidosqualene to lanosterol in the reaction that forms the sterol nucleus.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Seven binary protein-protein interactions (YIF1A, AQP6, CIB1, SLC10A1, SLC10A6, TMEM167B, TMEM86B) from a high-throughput yeast two-hybrid interactome map (HuRI), annotated as the uninformative parent term protein binding. Reason: "protein binding" (GO:0005515) conveys no specific molecular function and the interactions derive from a proteome-wide binary screen with no functional interpretation for LSS. The partners (several ER/membrane transporters and a trafficking factor) are consistent with LSS residing in the ER membrane but do not define a distinct function. Per curation policy the experimental IPI is retained but flagged as an over-annotation rather than removed. Supporting Evidence: file:human/LSS/LSS-uniprot.txt P48449; Q99828: CIB1; NbExp=3; IntAct=EBI-3930711, EBI-372594;
GO:0006695 cholesterol biosynthetic process	TAS Reactome:R-HSA-9969896	ACCEPT	Summary: Reactome traceable assertion placing LSS in cholesterol biosynthesis (the lanosterol biosynthesis module of the cholesterol pathway). Reason: Correct and authoritative. Reactome documents that cholesterol biosynthesis proceeds through lanosterol, the product of LSS; this is a core process role. Supporting Evidence: Reactome:R-HSA-9969896 Cholesterol biosynthesis begins with the transformation of cytosolic acetyl CoA into lanosterol in a sequence of 15 reactions
GO:0000250 lanosterol synthase activity	TAS Reactome:R-HSA-191366	ACCEPT	Summary: Reactome traceable assertion of the core catalytic function: LSS cyclizes squalene 2,3-epoxide to lanosterol. Reason: Correct and specific; matches the defining catalytic activity of LSS and all experimental evidence. Supporting Evidence: Reactome:R-HSA-191366 Lanosterol synthase (LSS) catalyzes the cyclization of squalene 2,3-epoxide to lanosterol, a reaction that forms the sterol nucleus
GO:0000250 lanosterol synthase activity	EXP PMID:14766201 The monotopic membrane protein human oxidosqualene cyclase i...	ACCEPT	Summary: Direct experimental demonstration of lanosterol synthase (oxidosqualene cyclase) activity using recombinant human OSC purified from Pichia pastoris, active as a monomer, with IC50 for the reference inhibitor matching human liver microsomal OSC. Reason: Gold-standard experimental support for the core molecular function. Supporting Evidence: PMID:14766201 The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC) catalyzes the formation of lanosterol the first sterol precursor of cholesterol in mammals.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:14766201 The monotopic membrane protein human oxidosqualene cyclase i...	ACCEPT	Summary: Experimental characterization of human OSC as a monotopic integral/peripheral membrane protein of the ER, active as a monomer. Reason: Directly supports ER-membrane localization; consistent with the crystallographic and disease-gene studies (PMID:15525992, PMID:30401459) and UniProt. Supporting Evidence: PMID:14766201 The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC) catalyzes the formation of lanosterol
GO:0005789 endoplasmic reticulum membrane	EXP PMID:15525992 Insight into steroid scaffold formation from the structure o...	ACCEPT	Summary: Crystal structures (PDB 1W6J, 1W6K) of the human membrane protein OSC, confirming it is a membrane-bound enzyme localized to the ER membrane. Reason: Structural study of the membrane-bound human enzyme corroborating ER-membrane localization and defining the active site of the cyclization reaction. Supporting Evidence: PMID:15525992 the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase)
GO:0005789 endoplasmic reticulum membrane	IDA PMID:30401459 Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, C...	ACCEPT	Summary: Immunofluorescence localization of wild-type LSS to the endoplasmic reticulum in keratinocytes; hypotrichosis-causing mutants are partly mislocalized outside the ER. Reason: Direct assay (IDA) confirming ER localization of LSS and showing that disease mutations disrupt correct ER localization. Supporting Evidence: PMID:30401459 wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER
GO:0000250 lanosterol synthase activity	IMP PMID:26200341 Lanosterol reverses protein aggregation in cataracts.	ACCEPT	Summary: Mutational evidence: two congenital-cataract LSS missense mutations (W581R, G588S) impair the catalytic function of LSS, demonstrating that LSS activity depends on these conserved residues. Reason: Supports the core molecular function through loss-of-function disease variants that abolish lanosterol synthase activity. Supporting Evidence: PMID:26200341 Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS.
GO:0000250 lanosterol synthase activity	IGI PMID:7639730 Molecular cloning of the human gene encoding lanosterol synt...	ACCEPT	Summary: Genetic complementation: the human LSS (OSC) gene rescued a yeast lanosterol synthase-deficient mutant (SMY8; yeast ERG7, UniProtKB:P38604), and a cell-free homogenate of the complemented strain converted 2,3-oxidosqualene to lanosterol. Reason: Functional (interspecies genetic interaction / complementation) evidence directly establishing that LSS encodes an active lanosterol synthase. Supporting Evidence: PMID:7639730 The yeast lanosterol synthase deficient mutant SMY8 was complemented by the human gene, and a cell-free homogenate of SMY8 expressing the human gene was shown to convert 2,3-oxidosqualene to lanosterol.
GO:0006694 steroid biosynthetic process	IMP PMID:26200341 Lanosterol reverses protein aggregation in cataracts.	KEEP AS NON CORE	Summary: Involvement of LSS in steroid/sterol biosynthesis, inferred from disease mutations that impair LSS catalytic function within the cholesterol synthesis pathway. Reason: Correct but general: steroid biosynthetic process is a broad parent of the more specific cholesterol/sterol biosynthetic process that captures the biologically precise role of LSS. Retain as a valid non-core annotation. Supporting Evidence: PMID:26200341 It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway.
GO:0031647 regulation of protein stability	IMP PMID:26200341 Lanosterol reverses protein aggregation in cataracts.	KEEP AS NON CORE	Summary: Annotation derived from the finding that LSS, through its product lanosterol, prevents intracellular aggregation of cataract-causing mutant crystallins and can reverse preformed lens protein aggregates. Reason: This is a downstream, indirect consequence of the LSS product lanosterol acting as a small-molecule chaperone on lens crystallins, not a direct molecular activity of LSS on protein stability. It is a genuine, disease-relevant phenotype but not a core function; retain as non-core. Supporting Evidence: PMID:26200341 Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: High-throughput mass-spectrometry detection of LSS in the membrane proteome of an NK-like cell line. Reason: The generic parent term "membrane" is subsumed by the specific, experimentally supported endoplasmic reticulum membrane localization (GO:0005789). It adds no information beyond the more precise calls and is uninformative on its own. Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins
GO:0005811 lipid droplet	IDA PMID:21498505 Human lysophosphatidylcholine acyltransferases 1 and 2 are l...	KEEP AS NON CORE	Summary: Lipid-droplet localization detected in a study of LPCAT1/2, in which LSS was identified among lipid-droplet-associated proteins. Reason: Lipid droplets bud from and remain contiguous with the ER, so monotopic ER enzymes such as LSS co-fractionate with LDs. Real but secondary to the core ER localization; retain as non-core. Supporting Evidence: PMID:21498505 both enzymes additionally localize to lipid droplets (LDs), which consist of a core of neutral lipids surrounded by a monolayer of phospholipid
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-1655828	ACCEPT	Summary: Reactome traceable assertion of ER-membrane localization (from the LSS expression event). Reason: Consistent with experimental ER-membrane localization; redundant with the EXP/IDA annotations but correct. Supporting Evidence: Reactome:R-HSA-191366 LSS is located on the ER membrane and is active in monomeric form
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-191366	ACCEPT	Summary: Reactome traceable assertion that LSS is located on the ER membrane and active as a monomer, in the lanosterol-forming cyclization reaction. Reason: Correct; matches experimental evidence for ER-membrane localization. Supporting Evidence: Reactome:R-HSA-191366 LSS is located on the ER membrane and is active in monomeric form
GO:0005811 lipid droplet	IDA PMID:14741744 Identification of major proteins in the lipid droplet-enrich...	KEEP AS NON CORE	Summary: LSS identified by proteomics in the lipid-droplet-enriched fraction isolated from the human hepatocyte cell line HuH7. Reason: Co-fractionation of an ER lipid enzyme with the lipid-droplet fraction is expected given ER-LD continuity. Genuine detection but a secondary compartment; retain as non-core relative to the core ER-membrane localization. Supporting Evidence: PMID:14741744 a fraction enriched with lipid droplets was isolated from a human hepatocyte cell line HuH7 using sucrose density gradient centrifugation
GO:0006695 cholesterol biosynthetic process	IMP PMID:17186944 Selective up-regulation of LXR-regulated genes ABCA1, ABCG1,...	ACCEPT	Summary: Involvement in cholesterol biosynthesis inferred from pharmacological inhibition of oxidosqualene:lanosterol cyclase (OSC/LSS), which reduced cholesterol synthesis and diverted flux toward the oxysterol LXR agonist 24(S),25-epoxycholesterol. Reason: Directly supports the core biological-process role of LSS in cholesterol biosynthesis; blocking LSS lowers cholesterol synthesis. Supporting Evidence: PMID:17186944 THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis

Gene Description

Existing Annotations Review

Core Functions

Lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase): catalyses the polycyclization of (S)-2,3-epoxysqualene to lanosterol at the endoplasmic reticulum membrane, forming the sterol nucleus and the committed precursor of cholesterol.

References

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