SERINC3 is a ubiquitously expressed multipass membrane protein and non-ATP-dependent phospholipid scramblase. Its two helical bundles mediate bidirectional transbilayer movement of phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine. At the plasma membrane, SERINC3 can be incorporated into budding retroviral particles; scrambling then exposes phosphatidylserine, disrupts viral-envelope lipid asymmetry, changes Env conformation, and reduces infectivity. HIV-1 Nef counteracts this intrinsic antiviral activity by removing SERINC3 from the cell surface and excluding it from virions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: The membrane annotation is correct but broader than the directly demonstrated plasma-membrane location. Reason: Human experiments establish SERINC3 at the plasma membrane, where its lipid-scrambling and virion-incorporation functions occur. The specific plasma-membrane term should replace generic membrane. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Proposed replacements: plasma membrane Supporting Evidence: file:human/SERINC3/SERINC3-uniprot.txt Cell membrane {ECO:0000269|PubMed:37474505} |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SERINC3 also traffics through or occupies Golgi membranes. Reason: The reviewed UniProt localization and mammalian orthology support a Golgi-membrane pool; this is compatible with normal trafficking of a multipass membrane protein. Supporting Evidence: file:human/SERINC3/SERINC3-uniprot.txt Golgi apparatus membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SERINC3 is a multipass plasma-membrane protein, the location from which it is incorporated into budding retroviral particles. Reason: Direct human imaging, structural work, and virion-incorporation experiments support plasma-membrane localization as integral to SERINC3 scramblase and antiviral functions. Supporting Evidence: PMID:37474505 The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The membrane annotation is correct but broader than the directly demonstrated plasma-membrane location. Reason: Human experiments establish SERINC3 at the plasma membrane, where its lipid-scrambling and virion-incorporation functions occur. The specific plasma-membrane term should replace generic membrane. Proposed replacements: plasma membrane Supporting Evidence: file:human/SERINC3/SERINC3-uniprot.txt Cell membrane {ECO:0000269|PubMed:37474505} |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: SERINC3 can accumulate in a perinuclear compartment after HIV-1 Nef-dependent redirection from the cell surface. Reason: The localization is supported but is principally infection-conditioned and reflects viral antagonism of the core plasma-membrane restriction activity, not the primary steady-state functional site. Supporting Evidence: file:human/SERINC3/SERINC3-uniprot.txt Cytoplasm, perinuclear region |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: A neurodegeneration-focused systematic interactome reports candidate SERINC3 interactions. Reason: The screening record does not establish a partner-specific biochemical activity of SERINC3. Generic protein binding is uninformative compared with the directly demonstrated scramblase activity. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: SERINC3 also traffics through or occupies Golgi membranes. Reason: The reviewed UniProt localization and mammalian orthology support a Golgi-membrane pool; this is compatible with normal trafficking of a multipass membrane protein. Supporting Evidence: file:human/SERINC3/SERINC3-uniprot.txt Golgi apparatus membrane |
| 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 direct work with purified human SERINC3 now identifies the specific molecular function as phospholipid scramblase activity. The evidence does not establish free-serine transmembrane transport by SERINC3. 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/SERINC3/SERINC3-deep-research-manual.md Evidence conclusion: SERINC3 is a non-ATP-dependent phospholipid scramblase at |
| GO:0005886 plasma membrane | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: SERINC3 is a multipass plasma-membrane protein, the location from which it is incorporated into budding retroviral particles. Reason: Direct human imaging, structural work, and virion-incorporation experiments support plasma-membrane localization as integral to SERINC3 scramblase and antiviral functions. Supporting Evidence: PMID:37474505 The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. |
| GO:0017121 plasma membrane phospholipid scrambling | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: Purified human SERINC3 directly flips multiple phospholipid classes across reconstituted membranes. Reason: The cryo-EM and purified-proteoliposome study directly establishes non-ATP-dependent phospholipid scramblase activity and connects it to phosphatidylserine exposure in viral envelopes. Supporting Evidence: PMID:37474505 purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. |
| GO:0017128 phospholipid scramblase activity | IDA PMID:37474505 Antiviral HIV-1 SERINC restriction factors disrupt virus mem... | ACCEPT | Summary: Purified human SERINC3 directly flips multiple phospholipid classes across reconstituted membranes. Reason: The cryo-EM and purified-proteoliposome study directly establishes non-ATP-dependent phospholipid scramblase activity and connects it to phosphatidylserine exposure in viral envelopes. Supporting Evidence: PMID:37474505 purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. |
| GO:0140374 antiviral innate immune response | IDA PMID:26416733 SERINC3 and SERINC5 restrict HIV-1 infectivity and are count... | ACCEPT | Summary: SERINC3 incorporation into retroviral envelopes reduces particle infectivity and is counteracted by viral Nef/GlycoGag proteins. Reason: Knockout/re-expression, virion-incorporation, infectivity, and lipid-scrambling experiments directly establish SERINC3 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: SERINC3 incorporation into retroviral envelopes reduces particle infectivity and is counteracted by viral Nef/GlycoGag proteins. Reason: Knockout/re-expression, virion-incorporation, infectivity, and lipid-scrambling experiments directly establish SERINC3 as a cell-intrinsic antiviral restriction factor. 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: SERINC3 incorporation into retroviral envelopes reduces particle infectivity and is counteracted by viral Nef/GlycoGag proteins. Reason: Knockout/re-expression, virion-incorporation, infectivity, and lipid-scrambling experiments directly establish SERINC3 as a cell-intrinsic antiviral restriction factor. Supporting Evidence: PMID:37474505 SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8932980 | ACCEPT | Summary: SERINC3 is a multipass plasma-membrane protein, the location from which it is incorporated into budding retroviral particles. Reason: Direct human imaging, structural work, and virion-incorporation experiments support plasma-membrane localization as integral to SERINC3 scramblase and antiviral functions. Supporting Evidence: PMID:37474505 The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. |
Loading supporting content…
Download this section (compressed HTML)Q: How is SERINC3 scramblase activity regulated in uninfected human cells without constitutively collapsing plasma-membrane lipid asymmetry?
Q: Do the two human SERINC3 isoforms differ in surface localization, phospholipid specificity, or retroviral restriction?
Q: Which human SERINC3 residues form the physiological lipid-translocation path, and can scrambling be separated from virion incorporation?
Experiment: Compare endogenous SERINC3-dependent leaflet lipidomics in plasma and Golgi membranes across signaling states, using knockout/rescue, matched surface-expression controls, and purified-protein reconstitution with candidate lipids and cofactors.
Hypothesis: SERINC3 scramblase activity is regulated by membrane context or a host cofactor absent from simple proteoliposomes.
Type: Leaflet-resolved lipidomics and regulated scramblase reconstitution
Experiment: Perform isoform-specific rescue in SERINC3-null human T cells, quantify topology and surface abundance, and measure lipid flipping, HIV-1 virion incorporation, phosphatidylserine exposure, and infectivity.
Hypothesis: Isoform 2 has altered topology or trafficking that reduces scrambling and antiviral activity.
Type: Isoform-resolved trafficking and antiviral complementation
Experiment: Introduce structure- and simulation-guided central-cavity mutations, require normal folding and surface expression, then compare purified lipid flipping, Nef binding/downregulation, virion incorporation, and restriction.
Hypothesis: A central hydrophilic pathway mediates scrambling independently of Nef-sensitive trafficking determinants.
Type: Structure-guided separation-of-function mutagenesis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The normal non-viral physiological consequences and regulation of SERINC3 phospholipid scrambling in human plasma and Golgi membranes are unclear.
OPEN BIOLOGY BP_DARK
What is known: Purified-protein and virion assays establish lipid flipping, but the evidence set does not identify the endogenous activating conditions, lipid-asymmetry outputs, or cellular pathway outside infection.
Significance: This is necessary to understand why a constitutively expressed scramblase does not simply erase membrane asymmetry in uninfected cells.
What would resolve it: Measure leaflet-resolved lipid distributions after endogenous SERINC3 knockout/rescue under candidate regulatory conditions, with matched surface abundance and catalysis-defective mutants.
Provenance (the field's own admissions):
Gap: The functional differences between Q13530-1 and the N-terminally truncated Q13530-2 isoform are unknown.
OPEN BIOLOGY MF_DARK
What is known: UniProt defines both sequences, but the structural, scrambling, and antiviral studies do not resolve which endogenous isoforms are present or active.
Significance: Isoform-specific topology or trafficking could alter lipid access, plasma-membrane abundance, and restriction potency.
What would resolve it: Express each isoform at matched levels after endogenous SERINC3 deletion and compare topology, glycosylation, surface trafficking, proteoliposome flipping, virion incorporation, and antiviral activity.
Provenance (the field's own admissions):
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)