SERINC5 is a multipass plasma-membrane phospholipid scramblase and intrinsic retroviral restriction factor. It mediates non-ATP-dependent bidirectional movement of phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine between membrane leaflets. SERINC5 is incorporated from the producer-cell surface into budding retroviral envelopes, where it disrupts phosphatidylserine asymmetry and inhibits subsequent particle entry. Phosphatidylserine exposure itself is not sufficient to explain restriction, whose proximal mechanism remains unresolved. HIV-1 Nef counteracts SERINC5 by redirecting it from the cell surface to an endosomal/perinuclear compartment and excluding it from virions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: SERINC5 is an integral membrane protein, but generic membrane is less informative than its directly demonstrated plasma-membrane site of action. Reason: SERINC5 is active at the producer-cell plasma membrane, where it scrambles phospholipids and is incorporated into budding retroviral particles. Replace the broad membrane term with plasma membrane. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Proposed replacements: plasma membrane Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SERINC5 is a multipass plasma-membrane protein, and the cell surface is the functional location from which it enters budding retroviral envelopes. Reason: Direct localization and virion-incorporation experiments independently support plasma-membrane localization, which is also consistent with the reviewed UniProt record and scramblase activity. Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-derived membrane annotation correctly captures SERINC5 topology but is broader than its directly demonstrated plasma-membrane location. Reason: Replace generic membrane with plasma membrane, the experimentally established location for SERINC5 scrambling, virion incorporation, and antiviral restriction. Proposed replacements: plasma membrane Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: SERINC5 accumulates in a perinuclear/endosomal compartment when HIV-1 Nef redirects it away from the cell surface. Reason: This localization is experimentally supported but principally represents viral antagonism of the core plasma-membrane activity rather than the normal primary functional site. Supporting Evidence: PMID:26416734 Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | UNDECIDED | Summary: HPA immunofluorescence reports cytosol signal, but the underlying primary image record is not present locally. Reason: SERINC5 is an obligate multipass membrane protein, so a soluble-cytosol assignment conflicts with established topology and may reflect unresolved internal membrane signal. Because the experimental record cannot be checked here, the conservative action is UNDECIDED rather than removal. Supporting Evidence: file:human/SERINC5/SERINC5-uniprot.txt Multi-pass membrane protein |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: SERINC5 is a multipass plasma-membrane protein, and the cell surface is the functional location from which it enters budding retroviral envelopes. Reason: Direct localization and virion-incorporation experiments independently support plasma-membrane localization, which is also consistent with the reviewed UniProt record and scramblase activity. Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0140104 molecular carrier activity | EXP PMID:16120614 Serinc, an activity-regulated protein family, incorporates s... | MODIFY | Summary: The older Serinc-family study described carrier-like incorporation of serine into membrane lipid synthesis. Reason: Molecular carrier activity is too broad, and the abstract does not establish free-serine transmembrane transport by human SERINC5. Direct human work identifies the specific molecular function as phospholipid scramblase activity. Proposed replacements: phospholipid scramblase activity Supporting Evidence: PMID:16120614 facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. PMID:37474505 purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. file:human/SERINC5/SERINC5-deep-research-manual.md Evidence conclusion: SERINC5 is a non-ATP-dependent phospholipid scramblase at the plasma membrane and in retroviral envelopes. |
| GO:0005886 plasma membrane | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: SERINC5 is a multipass plasma-membrane protein, and the cell surface is the functional location from which it enters budding retroviral envelopes. Reason: Direct localization and virion-incorporation experiments independently support plasma-membrane localization, which is also consistent with the reviewed UniProt record and scramblase activity. Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0017121 plasma membrane phospholipid scrambling | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: Human SERINC5 directly redistributes phospholipids between membrane leaflets and exposes phosphatidylserine on retroviral particles. Reason: Purified-protein/reconstituted-membrane assays and independent virion asymmetry measurements support SERINC5 phospholipid scrambling. The later mechanistic study confirms scrambling while separating it from the still-unresolved cause of antiviral restriction. Supporting Evidence: PMID:37474505 purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. PMID:38785977 This asymmetry is completely lost upon incorporation of SER5 or TMEM16F. |
| GO:0017128 phospholipid scramblase activity | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: Human SERINC5 directly redistributes phospholipids between membrane leaflets and exposes phosphatidylserine on retroviral particles. Reason: Purified-protein/reconstituted-membrane assays and independent virion asymmetry measurements support SERINC5 phospholipid scrambling. The later mechanistic study confirms scrambling while separating it from the still-unresolved cause of antiviral restriction. Supporting Evidence: PMID:37474505 purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. PMID:38785977 This asymmetry is completely lost upon incorporation of SER5 or TMEM16F. |
| GO:0140374 antiviral innate immune response | IDA PMID:26416733 SERINC3 and SERINC5 restrict HIV-1 infectivity and are count... | ACCEPT | Summary: SERINC5 is incorporated into retroviral particles and potently restricts their subsequent infectivity; HIV-1 Nef counteracts this activity. Reason: Knockdown, knockout, re-expression, replication, and virion-incorporation experiments directly establish SERINC5 as a cell-intrinsic antiviral restriction factor. Supporting Evidence: PMID:26416733 SERINC3 and SERINC5 together restricted HIV-1 replication |
| GO:0140374 antiviral innate immune response | IDA PMID:26416734 HIV-1 Nef promotes infection by excluding SERINC5 from virio... | ACCEPT | Summary: Plasma-membrane SERINC5 enters budding HIV-1 particles and impairs entry into target cells. Reason: This independent discovery study directly identifies SERINC5 as a potent HIV-1 restriction factor and shows that Nef antagonizes it by endosomal redirection. Supporting Evidence: PMID:26416734 SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity |
| GO:0140374 antiviral innate immune response | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: SERINC5 incorporation into HIV-1 and MLV particles reduces infectivity and is counteracted by viral accessory proteins. Reason: Virion phosphatidylserine exposure, Env-conformation, and infectivity experiments support antiviral restriction. Later work confirms restriction but shows that external phosphatidylserine alone is not its direct cause. Supporting Evidence: PMID:37474505 SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity PMID:38785977 PS externalization is likely not the key driver for infectivity reduction by SER5. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8932980 | ACCEPT | Summary: SERINC5 is a multipass plasma-membrane protein, and the cell surface is the functional location from which it enters budding retroviral envelopes. Reason: Direct localization and virion-incorporation experiments independently support plasma-membrane localization, which is also consistent with the reviewed UniProt record and scramblase activity. Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0005886 plasma membrane | IDA PMID:26416733 SERINC3 and SERINC5 restrict HIV-1 infectivity and are count... | ACCEPT | Summary: SERINC5 is a multipass plasma-membrane protein, and the cell surface is the functional location from which it enters budding retroviral envelopes. Reason: Direct localization and virion-incorporation experiments independently support plasma-membrane localization, which is also consistent with the reviewed UniProt record and scramblase activity. Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0005886 plasma membrane | IDA PMID:26416734 HIV-1 Nef promotes infection by excluding SERINC5 from virio... | ACCEPT | Summary: SERINC5 is a multipass plasma-membrane protein, and the cell surface is the functional location from which it enters budding retroviral envelopes. Reason: Direct localization and virion-incorporation experiments independently support plasma-membrane localization, which is also consistent with the reviewed UniProt record and scramblase activity. Supporting Evidence: PMID:26416734 SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | UNDECIDED | Summary: A large-scale urinary-exosome proteomics study is the source of this high-throughput localization row. Reason: The locally cached record is abstract-only and its accessible text does not identify SERINC5 among the 1,132 detected proteins. Without the protein table or full experimental record, the SERINC5-specific detection cannot be verified or rejected. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0006658 phosphatidylserine metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mammalian orthology and older Serinc-family work support a possible contribution to serine-derived lipid synthesis. Reason: Retain this broad transferred process as a plausible non-core physiological consequence. The cited family-level abstract and reviewed UniProt support enhanced phosphatidylserine/sphingolipid synthesis, but direct human evidence establishes scrambling rather than biosynthesis as SERINC5's proximal molecular activity. Supporting Evidence: PMID:16120614 facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. |
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Download this section (compressed HTML)Q: Which membrane or Env property, rather than phosphatidylserine exposure itself, is the proximal determinant of SERINC5-mediated retroviral restriction?
Q: How is SERINC5 scramblase activity regulated in uninfected human cells without constitutively collapsing plasma-membrane lipid asymmetry?
Q: Do the four human SERINC5 isoforms differ in localization, lipid specificity, Nef sensitivity, virion incorporation, or restriction potency?
Experiment: Combine leaflet-resolved virion lipidomics, super-resolution membrane-domain imaging, Env conformational assays, and staged fusion measurements across SERINC5-sensitive and -resistant envelopes, with matched virion incorporation and lipid-exchange controls.
Hypothesis: SERINC5 restricts retroviral entry through redistribution of lipids or membrane nanodomains other than external phosphatidylserine.
Type: Mechanism-resolved virion membrane and entry analysis
Experiment: Compare endogenous SERINC5-dependent leaflet lipid distributions across signaling and differentiation states, then reconstitute purified SERINC5 with candidate lipids and cofactors while controlling orientation and protein copy number.
Hypothesis: SERINC5 scrambling is regulated by membrane context or a host cofactor absent from purified proteoliposomes.
Type: Regulated scramblase reconstitution and cellular lipid asymmetry profiling
Experiment: Introduce structure-guided mutations, require normal folding and plasma-membrane abundance, and assay purified lipid flipping, Nef-dependent downregulation, virion incorporation, Env remodeling, and infectivity to identify separation-of-function alleles.
Hypothesis: SERINC5 contains separable structural determinants for lipid scrambling, Nef-mediated trafficking, and antiviral restriction.
Type: Structure-guided separation-of-function mutagenesis
Experiment: Perform isoform-specific rescue in SERINC5-null human T cells and compare topology, glycosylation, surface abundance, lipid scrambling, Nef sensitivity, virion incorporation, and HIV-1 restriction.
Hypothesis: Alternative SERINC5 isoforms have distinct trafficking and antiviral activities.
Type: Isoform-resolved trafficking and antiviral complementation
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular mechanism by which virion-incorporated SERINC5 restricts entry remains unresolved.
OPEN BIOLOGY MF_DARK
What is known: SERINC5 scrambling, phosphatidylserine exposure, and restriction are established, but direct lipid manipulation shows that external phosphatidylserine level does not determine restriction potency.
Significance: Resolving the proximal mechanism is necessary to connect SERINC5's membrane activity to its potent envelope-dependent antiviral phenotype.
What would resolve it: Use separation-of-function mutants and controlled virion lipid manipulation to test effects on multiple lipid species, nanodomain organization, Env conformation, fusion intermediates, and infectivity while matching surface abundance and virion incorporation.
Provenance (the field's own admissions):
Gap: The physiological regulation and non-viral cellular consequences of SERINC5 scrambling are unknown.
OPEN BIOLOGY BP_DARK
What is known: Purified-protein and virion assays establish lipid flipping, but the evidence set does not identify endogenous activating conditions or leaflet-lipid outputs in uninfected human cells.
Significance: A constitutively active plasma-membrane scramblase would be expected to perturb lipid asymmetry, so its normal regulation and cellular purpose are central to understanding SERINC5 biology.
What would resolve it: Quantify endogenous SERINC5-dependent leaflet lipid distributions across cell states with knockout/rescue, matched surface-expression controls, and catalysis-defective mutants.
Provenance (the field's own admissions):
Gap: Functional differences among the four human SERINC5 isoforms are not established.
OPEN BIOLOGY MF_DARK
What is known: Reviewed UniProt defines Q86VE9-1 through Q86VE9-4, but the cited functional studies do not resolve isoform-specific expression, topology, scrambling, trafficking, Nef sensitivity, or restriction.
Significance: Alternative sequence segments could alter membrane topology, trafficking, virion incorporation, and antiviral potency.
What would resolve it: Compare all four isoforms under matched expression after endogenous SERINC5 deletion, using topology, surface-trafficking, lipid-flipping, Nef-downregulation, virion-incorporation, and infectivity assays.
Provenance (the field's own admissions):
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