Affinage

SERINC5

Serine incorporator 5 · UniProt Q86VE9

Length
423 aa
Mass
47.0 kDa
Annotated
2026-06-10
84 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SERINC5 is a multi-pass plasma membrane protein that functions as a broad-spectrum antiviral restriction factor against enveloped viruses, acting principally by incorporating into budding virions and blocking virus-cell membrane fusion (PMID:26416733, PMID:26416734, PMID:28179429). Incorporated SERINC5 inhibits the formation and stabilizes against collapse of small fusion pores, promotes spontaneous functional inactivation of sensitive HIV-1 Env glycoproteins, and exposes conserved gp41 domains that sensitize virions to neutralizing antibodies (PMID:28179429, PMID:35891369). It alters Env conformation directly, preferentially engaging open-conformation trimers and dissociating them, with CD4-induced opening rendering otherwise resistant Env sensitive (PMID:31043528, PMID:32796070). Rather than changing bulk lipid composition, SERINC5 restricts fusion by increasing viral membrane order, rigidity, and heterogeneity in a phosphatidylserine-sensitive manner, and can act from the target-cell membrane as well as the producer cell (PMID:28659343, PMID:36946615, PMID:41247072). Antiviral activity requires plasma membrane localization conferred by the C-terminal tenth transmembrane domain and partitioning into lipid rafts, and an aromatic residue at position 412 (PMID:28275190, PMID:29268082, PMID:34190600). Beyond direct fusion blockade, SERINC5 has separable activities against other viruses, including blocking influenza HA-mediated fusion by destabilizing its pre-fusion conformation, inhibiting SARS-CoV-2 and HBV entry/secretion, and repressing HIV-1 LTR transcription by recruiting TRIM40 to degrade MDA5/RIG-I and dampen NF-κB signaling (PMID:36409124, PMID:35618710, PMID:32431673, PMID:39653243). Diverse retroviruses counteract SERINC5 through convergent strategies: HIV-1/SIV Nef, MLV glycoGag, and EIAV S2 each bind SERINC5 and drive its ubiquitin-dependent endolysosomal degradation, redirecting it from the plasma membrane and excluding it from virions (PMID:26416733, PMID:26416734, PMID:29514909, PMID:30862674). Nef sensitivity is governed by intracellular loop 4, including a palmitoylated tri-cysteine motif and a protective EDTEE acidic cluster, with Nef homodimers bridging SERINC5 to AP-2 for clathrin-mediated endocytosis in a process requiring CDK13-dependent phosphorylation at S360 [PMID:29386131, PMID:31941773, PMID:bio_10.1101_2025.10.27.684794, PMID:32873704, PMID:34380030]. SERINC5 surface levels are further set by Cul3-KLHL20-mediated K33/K48 polyubiquitination at K130, while MLV glycoGag additionally triggers RETREG1-dependent micro-ER-phagy of ER-retained SERINC5 (PMID:35474067, PMID:41066524). SERINC5 also has a virus-independent developmental role, repressing chondrocyte proliferation by inhibiting Sox9 transcriptional activity (PMID:39568258).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2015 High

    Established SERINC5 as an endogenous host restriction factor whose incorporation into HIV-1 virions reduces infectivity and is the target of Nef and glycoGag, answering why these viral accessory proteins enhance particle infectivity.

    Evidence RNAi silencing, CRISPR double-knockout CD4+ T cells, virion incorporation and infectivity assays, plus Rab7-colocalization imaging across primate Nefs

    PMID:26416733 PMID:26416734

    Open questions at the time
    • Molecular mechanism of infectivity reduction not yet defined
    • How Nef physically engages SERINC5 unresolved at this stage
  2. 2017 High

    Defined the antiviral mechanism as a block at the membrane fusion step, showing SERINC5 inhibits small fusion pore formation and triggers Env conformational inactivation rather than binding Env directly in producer cells.

    Evidence Single-virus lipid-mixing fusion assay, neutralization with anti-gp41 antibodies/peptides, and negative co-IP for direct SERINC5–Env interaction

    PMID:28179429

    Open questions at the time
    • Did not establish whether SERINC5 contacts Env directly
    • Did not identify the biophysical change in the viral membrane
  3. 2017 High

    Localized antiviral activity to the plasma membrane and lipid rafts and separated virion incorporation from Env-altering function via chimeric mapping, defining the cell-biological requirements for restriction.

    Evidence C-terminal TM10 deletion mutants, isoform analysis, detergent-resistant membrane fractionation, and SERINC5/SERINC2 chimeras with infectivity readouts

    PMID:28275190 PMID:29268082

    Open questions at the time
    • Precise residues mediating Env conformational change not yet mapped
    • DRM mapping was Medium-confidence single-lab
  4. 2017 High

    Ruled out a lipid-metabolic (serine incorporation) mechanism by showing no steady-state lipid compositional change, redirecting the field toward a physical/conformational model.

    Evidence Quantitative lipid mass spectrometry of virions and producer cells, including phosphatidylserine surface assay

    PMID:28659343

    Open questions at the time
    • Did not exclude transient or local lipid reorganization within the membrane
  5. 2018 High

    Resolved how Nef removes SERINC5, demonstrating direct membrane-dependent binding, clathrin/AP-2-dependent endocytosis, ubiquitin-chain requirements, and sequential endosomal trafficking to lysosomes.

    Evidence BiFC, AP-2 knockdown, dominant-negative Rabs, ubiquitin linkage mutants, bafilomycin rescue, and LAMP1 colocalization

    PMID:29514909

    Open questions at the time
    • Did not identify the cellular E3 ligase ubiquitinating SERINC5
    • Did not define the SERINC5 determinant of Nef binding
  6. 2018 High

    Mapped the determinant of Nef sensitivity to intracellular loop 4 while showing intrinsic restriction is conserved across orthologs, separating antagonism susceptibility from antiviral activity.

    Evidence Reciprocal ICL4 domain swaps between Nef-sensitive and Nef-resistant orthologs with infectivity assays

    PMID:29386131

    Open questions at the time
    • Specific ICL4 residues engaged by Nef not yet identified
  7. 2018 Medium

    Characterized SERINC5 N-glycosylation at N294, distinguishing virion (complex glycan) from cellular (high-mannose) forms and linking glycosylation to stability but not to restriction or Nef sensitivity.

    Evidence Glycosidase treatment, N294A mutagenesis, proteasome/lysosome inhibitor rescue, Western blot

    PMID:30158294

    Open questions at the time
    • Single lab
    • Functional role of differential virion glycosylation unresolved
  8. 2019 Medium

    Showed that an unrelated lentiviral antagonist, EIAV S2, converges on the same SERINC5 endolysosomal degradation pathway, generalizing the Nef-like counteraction strategy.

    Evidence BiFC, co-IP, myristoylation-deficient mutants, endocytosis inhibitors, and ubiquitin mutants

    PMID:30862674

    Open questions at the time
    • Single lab
    • S2 binding site on SERINC5 not mapped
  9. 2019 Medium

    Demonstrated a direct, conformation-selective SERINC5–Env interaction, reconciling earlier negative co-IP by showing preference for open trimers and CD4-induced sensitization of closed Env.

    Evidence BiFC, co-IP, and single-round infectivity with CD4+/CD4- cells using tier 1 vs tier 2/3 Envs

    PMID:31043528

    Open questions at the time
    • Single lab; apparent conflict with earlier negative co-IP not fully reconciled
    • Structural basis of trimer dissociation unknown
  10. 2020 High

    Characterized endogenous SERINC5 (CRISPR HA knock-in) confirming lipid-raft localization and virion incorporation, and established interferon-alpha-driven JAK-dependent surface upregulation as a regulatory input.

    Evidence CRISPR knock-in tagging, raft fractionation, flow cytometry, ruxolitinib treatment, virion incorporation blot

    PMID:31597782

    Open questions at the time
    • Mechanism of IFN-driven surface increase (without mRNA change) not defined
  11. 2020 Medium

    Defined how SERINC5 alters Env structure and how it resists Nef, identifying gp120 conformational changes upon restriction and an EDTEE acidic cluster conferring partial, Nef-specific resistance.

    Evidence Virion-capture antibody panel binding assays and EDTEE deletion mutagenesis with surface/virion/infectivity readouts

    PMID:31941773 PMID:32796070

    Open questions at the time
    • Single-lab studies
    • EDTEE does not affect glycoGag antagonism, leaving glycoGag determinants open
  12. 2020 Medium

    Extended SERINC5 antiviral scope to HBV via a distinct, glycosylation-interfering mechanism in the Golgi, showing functional domains separable from HIV-1 restriction.

    Evidence Overexpression/knockdown infectivity, envelope glycosylation analysis, Golgi co-localization, domain deletion

    PMID:32431673

    Open questions at the time
    • Single lab
    • Mechanism by which SERINC5 alters HBV envelope glycosylation unresolved
  13. 2021 High

    Resolved the structural mechanism of Nef antagonism, showing Nef homodimers bridge SERINC5 to AP-2 and that CDK13-mediated S360 phosphorylation licenses Nef–SERINC5 engagement and surface downregulation.

    Evidence Dimer-interface mutagenesis with BiFC/colocalization/infectivity, and AP/MS plus CDK13 kinase assay with S360A/S360E and CD8-SERINC5 chimeras

    PMID:32873704 PMID:34380030

    Open questions at the time
    • Whether S360 phosphorylation has roles beyond Nef antagonism unknown
    • Kinase regulating S360 in absence of Nef not defined
  14. 2021 Medium

    Linked SERINC5 restriction to innate immune signaling outputs, showing it potentiates proinflammatory cytokine responses to HIV-1 particles and acts via MDA5 against CSFV.

    Evidence Primary macrophage/DC infection with cytokine ELISA and entry controls; yeast two-hybrid, co-IP, MDA5 knockdown, IFN reporter for CSFV

    PMID:33013817 PMID:33597208

    Open questions at the time
    • Single-lab studies
    • Relationship between fusion-block and immune-signaling functions not integrated
  15. 2021 Medium

    Identified an aromatic residue at position 412 as essential for retroviral restriction and antibody sensitization while being dispensable for localization and virion incorporation, pinpointing a functional determinant of the fusion-blocking activity.

    Evidence Systematic F412 mutagenesis with multi-Env infectivity, neutralization, surface flow cytometry, and virion incorporation blots

    PMID:34190600

    Open questions at the time
    • Single lab
    • Mechanistic role of the aromatic side chain in membrane/Env perturbation unknown
  16. 2022 High

    Generalized SERINC5 as a fusion-blocking restriction factor for unrelated enveloped viruses (influenza A, SARS-CoV-2) and revealed virus-specific antagonists (ORF7a) and conformational mechanisms on HA.

    Evidence smFRET on IAV HA dynamics, cell-cell and pseudovirus fusion assays, HA glycosylation mutagenesis, and SARS-CoV-2 infection/virion incorporation assays

    PMID:35618710 PMID:36409124

    Open questions at the time
    • SARS-CoV-2 study was Medium-confidence overexpression-based
    • Whether a single biophysical mechanism underlies all viruses untested
  17. 2022 High

    Identified the Cul3-KLHL20 E3 ligase and K130 as the regulatory hub controlling SERINC5 surface levels, with K33-linked chains driving trafficking and K48 chains driving degradation.

    Evidence Co-IP, linkage-specific ubiquitin mutants, K130R mutagenesis, Cul3/KLHL20 knockout, fractionation, surface flow cytometry

    PMID:35474067

    Open questions at the time
    • Whether KLHL20 regulation intersects with Nef-driven degradation unknown
    • Single lab
  18. 2022 Medium

    Quantified the kinetics of Env inactivation and refined the model that SERINC5 destabilizes sensitive Env conformations, using CD4-mimetics and conformation inhibitors as probes.

    Evidence Env inactivation kinetics, resistant/sensitive Env panel, CD4-mimetic and small-molecule conformation inhibitor treatments

    PMID:35891369

    Open questions at the time
    • Single lab
    • How SERINC5 mechanistically stabilizes/destabilizes specific Env states unresolved
  19. 2023 Medium

    Provided the biophysical basis of fusion inhibition, showing SERINC5 raises viral membrane order and heterogeneity and that phosphatidylserine reverses both the order change and the fusion block.

    Evidence Cryo-EM membrane thickness, FLIPPER-TR order probe, TIRF single-particle fusion, and PS/PE rescue experiments

    PMID:36946615

    Open questions at the time
    • Single lab
    • Direct link between altered membrane order and pore destabilization not formally proven
  20. 2024 Medium

    Uncovered a transcription-level antiviral arm and a non-viral developmental role, showing SERINC5 recruits TRIM40 to degrade MDA5/RIG-I and suppress NF-κB-driven HIV-1 LTR activity, and represses Sox9-driven chondrocyte programs.

    Evidence LTR reporter, TRIM40-MDA5/RIG-I co-IP and K48 ubiquitination, nuclear fractionation; and scRNA-seq, ChIP-seq, ATAC-seq, Sox9 reporter in chondrocytes

    PMID:39568258 PMID:39653243

    Open questions at the time
    • Single-lab studies
    • Apparent tension between SERINC5 enhancing (CSFV) vs degrading (HIV-1 transcription) MDA5/RIG-I unreconciled
    • Mechanism by which a TM protein regulates Sox9 unclear
  21. 2025 High

    Refined the antagonism determinants and revealed a second, organelle-specific degradation route, identifying a palmitoylated ICL4 tri-cysteine motif required for Nef antagonism and RETREG1-dependent micro-ER-phagy used by MLV glycoGag.

    Evidence Structure-guided ICL4 mutagenesis and palmitoylation assay (preprint); CRISPR knockouts of RETREG1/autophagy genes, co-IP, K130R ER-retention mutant, AP/MS

    PMID:41066524 PMID:bio_10.1101_2025.10.27.684794

    Open questions at the time
    • Tri-cysteine palmitoylation work is a preprint
    • How palmitoylation status modulates Nef engagement biochemically untested
  22. 2025 Medium

    Showed SERINC5 can restrict from the target cell membrane, not only the producer cell, by destabilizing fusion pores in a phosphatidylserine-reversible manner without altering CD4/co-receptor complexes.

    Evidence Fusion-from-without cell-cell fusion, single-particle pseudovirus fusion, receptor flow cytometry, PS rescue, lipid-mixing assays

    PMID:41247072

    Open questions at the time
    • Single lab
    • Physiological contribution of target-cell SERINC5 in vivo unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SERINC5 mechanistically unifies its diverse activities—membrane biophysical alteration, direct Env/HA conformational destabilization, transcriptional NF-κB control, and chondrocyte Sox9 repression—within a single transmembrane protein, and whether these reflect distinct domains or a common molecular activity.
  • No structure of SERINC5 alone or with Env/HA reported in the corpus
  • No reconstituted system establishing the primary biochemical activity
  • Opposing effects on MDA5/RIG-I across viral contexts not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
AP-2CDK13ENVKLHL20MDA5NEFRETREG1TRIM40

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 SERINC5 (and SERINC3) are incorporated into budding HIV-1 virions at the plasma membrane and potently inhibit HIV-1 particle infectivity; HIV-1 Nef and MLV glycoGag counteract this restriction by preventing SERINC5 incorporation into virions, an effect that precisely phenocopies SERINC3/SERINC5 double knockout. Silencing (RNAi), double-knockout CD4+ T cells (CRISPR/gene editing), virion incorporation assays, infectivity assays Nature High 26416733 26416734
2015 Nef redirects SERINC5 from the plasma membrane to a Rab7-positive late endosomal compartment, thereby excluding it from HIV-1 particles; this Nef activity is conserved across diverse primate immunodeficiency virus Nefs and is functionally mimicked by the structurally unrelated MLV glycoGag. Fluorescence microscopy (Rab7-colocalization), virion incorporation assays, cross-species Nef functional comparison Nature High 26416733 26416734
2017 SERINC5 incorporation into virions inhibits formation of small fusion pores between HIV-1 and target cells, promotes spontaneous functional inactivation of sensitive Env glycoproteins (but not resistant ones), increases exposure of conserved gp41 domains, and sensitizes virus to neutralizing antibodies and gp41-derived inhibitory peptides—without detectable direct SERINC5–Env co-immunoprecipitation. Single-virus fusion assay (fluorescent lipid mixing), neutralization assays with anti-gp41 antibodies and peptides, co-immunoprecipitation (negative result for direct interaction) The Journal of biological chemistry High 28179429
2017 The 10th transmembrane domain of SERINC5-001 is required for stable protein expression and plasma membrane localization; isoforms lacking this domain are unstable, localize to the cytoplasm, and lack anti-HIV-1 activity, establishing that plasma membrane localization is necessary for SERINC5 antiviral function. C-terminal deletion mutagenesis, RT-qPCR isoform quantification, subcellular fractionation/imaging, infectivity assays Journal of virology High 28275190
2018 Nef binds directly to SERINC5 in living cells (bimolecular fluorescence complementation), requires membrane association for this interaction, internalizes SERINC5 via receptor-mediated endocytosis (clathrin-dependent), and targets ubiquitinated SERINC5 sequentially through Rab5+ early, Rab7+ late, and Rab11+ recycling endosomes to LAMP1+ lysosomes for degradation; both K48- and K63-linked ubiquitin chains are required. Bimolecular fluorescence complementation (BiFC), NH4Cl/bafilomycin A1 rescue, dominant-negative Rab constructs, AP-2 knockdown, ubiquitin linkage-specific mutants, LAMP1 colocalization Journal of virology High 29514909
2017 SERINC5 localizes to detergent-resistant membranes (lipid rafts) in producer cells and its localization there correlates with its HIV-1 restriction activity; chimeric SERINC5/SERINC2 experiments revealed two separable functional domains: one for virion incorporation and one for changing Env conformation, localizing to DRMs, and blocking infection. Detergent-resistant membrane fractionation, chimeric protein analysis, 'fate of the capsid' assay, HIV-1 pseudovirus infectivity assays Virology Medium 29268082
2017 SERINC5-mediated restriction of HIV-1 infectivity is not associated with alterations in steady-state lipid composition (including phosphatidylserine) of producer cells or HIV-1 particles, arguing against a mechanism involving serine incorporation into membrane lipids. Quantitative lipid mass spectrometry of purified virions and producer cells, sphingosine metabolism kinetics, phosphatidylserine surface assay The Journal of biological chemistry High 28659343
2018 SERINC5 is N-glycosylated primarily at residue N294 with complex glycans in its virion-associated form, while the majority of cellular SERINC5 carries high-mannose glycans; N-glycosylation is required for steady-state protein stability (non-glycosylated N294A undergoes proteasomal degradation) but is not required for restrictive activity or sensitivity to Nef. Glycosidase treatment, site-directed mutagenesis (N294A), MG132 and bafilomycin A1 treatment, Western blot Journal of virology Medium 30158294
2018 The intracellular loop 4 (ICL4) of SERINC5 determines sensitivity to Nef; replacing ICL4 of a Nef-resistant SERINC5 with that of Nef-sensitive human SERINC5 conferred Nef sensitivity, and vice versa, while the anti-HIV-1 activity itself was conserved across vertebrate SERINC5 orthologs. Domain-swap chimeric proteins between Nef-sensitive and Nef-resistant SERINC5 orthologs, infectivity assays Cell reports High 29386131
2019 EIAV S2 protein interacts directly with SERINC5 (detected by BiFC and immunoprecipitation), requires myristoylation at its N-terminal glycine for this interaction (likely at the plasma membrane), internalizes SERINC5 via receptor-mediated endocytosis to endosomes and lysosomes, and induces ubiquitination-dependent SERINC5 degradation—similar to but more potent than HIV-1 Nef and MLV glycoMA. BiFC, co-immunoprecipitation, myristoylation-deficient mutant analysis, endocytosis inhibitors, ubiquitin mutants The Journal of biological chemistry Medium 30862674
2019 SERINC5 directly interacts with HIV-1 Env; SERINC5 preferentially interacts with open-conformation Env trimers (tier 1 NL Env) versus closed-conformation (tier 2/3 AD8 Env), dissociates the Env trimeric complex, and CD4 expression opens the closed Env conformation to allow SERINC5 to interact with and dissociate tier 2/3 Env trimers, rendering them sensitive to restriction. Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, single-round infectivity assay with CD4+ and CD4- cells Journal of virology Medium 31043528
2020 Endogenous SERINC5 protein (detected via CRISPR-knocked-in HA tag) localizes predominantly to lipid rafts, is present as a 35 kDa species in HIV-1 ΔNef virions, and IFN-α treatment increases SERINC5 cell surface levels in a JAK-dependent (ruxolitinib-sensitive) manner without changing total protein or mRNA levels. CRISPR/Cas9 knock-in HA tag, lipid raft fractionation, flow cytometry, ruxolitinib treatment, virion incorporation Western blot Journal of virology High 31597782
2020 A conserved acidic-cluster motif (EDTEE) in a cytoplasmic loop of SERINC5 confers partial resistance to Nef-mediated antagonism by limiting Nef-driven cell surface removal and virion exclusion, but does not affect intrinsic restriction activity; this resistance is Nef-specific and does not affect glycoGag-mediated antagonism. EDTEE deletion mutagenesis, cell surface flow cytometry, virion incorporation assay, infectivity assay Journal of virology Medium 31941773
2020 Nef homodimers (mediated by conserved dimer interface residues Leu112, Tyr115, Phe121) are required for SERINC5 downregulation, trafficking to Rab7+ late endosomes, and exclusion from virions; dimerization-defective Nef mutants retained interaction with both SERINC5 and AP-2 but failed to bridge them for productive endocytosis, supporting a model in which the Nef dimer bridges SERINC5 to AP-2. Crystal structure-guided mutagenesis of Nef dimer interface, BiFC dimerization assay, cell surface flow cytometry, Rab7 colocalization, virion incorporation assay, infectivity in 293T/Jurkat/primary PBMCs The Journal of biological chemistry High 32873704
2021 HIV-1 Nef associates with cyclin K (CycK)/CDK13 kinase complex; CDK13 phosphorylates SERINC5 at serine 360 (S360), and this phosphorylation is required for Nef to downregulate SERINC5 from the cell surface and counteract its antiviral activity; S360 phosphorylation increases Nef–SERINC5 interaction as shown by CD8–SERINC5 chimera experiments. Affinity purification/mass spectrometry, CDK13 kinase assay, S360A/S360E mutagenesis, CD8–SERINC5 chimera, cell surface flow cytometry, infectivity assay Cell reports High 34380030
2022 Cullin3-KLHL20 E3 ubiquitin ligase (localized at the trans-Golgi network) polyubiquitinates SERINC5 at lysine 130 via K33/K48-linked ubiquitin chains; K33-linked ubiquitination regulates SERINC5 trafficking to the plasma membrane (K130R retains SERINC5 in cytoplasm), while K48-linked ubiquitination contributes to its degradation from the cell surface. Co-immunoprecipitation, ubiquitin linkage-specific mutants, K130R mutagenesis, Cul3/KLHL20 knockout, subcellular fractionation, cell surface flow cytometry Nature communications High 35474067
2022 SERINC5 inhibits SARS-CoV-2 entry by blocking virus-cell fusion; SARS-CoV-2 ORF7a counteracts the antiviral effect of SERINC5 by blocking incorporation of overexpressed SERINC5 into budding SARS-CoV-2 virions. Overexpression of SERINC5 with SARS-CoV-2 infection assay, virion incorporation assay, fusion assay Nature communications Medium 35618710
2022 SERINC5 inhibits influenza A virus (IAV) infection by blocking HA-induced membrane fusion; smFRET analysis showed SERINC5 destabilizes the pre-fusion conformation of IAV HA and inhibits coiled-coil formation during membrane fusion; different HA subtypes exhibit varying sensitivity to SERINC5, and HA glycosylation site mutations affect sensitivity. Pseudovirus and authentic IAV infectivity assay, single-molecule FRET (smFRET) on HA conformational dynamics, cell-cell fusion assay, HA glycosylation site mutagenesis mBio High 36409124
2022 SERINC5 incorporation into virions accelerates functional inactivation of sensitive HIV-1 Env glycoproteins in a manner that correlates with fold reduction in infectivity; a CD4-mimetic compound sensitizes Env to SERINC5-mediated inactivation; SERINC5 may stabilize the closed Env trimer conformation in laboratory-adapted strains. Env inactivation kinetics assay, panel of resistant/sensitive Env mutants, CD4-mimetic compound treatment, small-molecule Env conformation inhibitor Viruses Medium 35891369
2023 SERINC5 increases membrane heterogeneity and order (larger fraction of ordered phase) in HIV pseudoviral membranes as measured by cryo-EM and fluorescent order probe (FLIPPER-TR); phosphatidylserine (PE treatment) rescues HIV fusion from SERINC5 restriction and decreases membrane order, suggesting SERINC5 restricts fusion by altering membrane biophysical properties including lipid chain order, rigidity, and lateral pressure. Cryo-electron microscopy (membrane thickness), FLIPPER-TR lipid order probe, TIRF-based single-particle fusion assay, phosphatidylserine/phosphatidylethanolamine rescue experiments ACS infectious diseases Medium 36946615
2020 SERINC5 inhibits HBV virion secretion by interfering with the glycosylation of HBV envelope proteins (LHB, MHB, SHB), increasing their non-glycosylated forms; SERINC5 co-localizes with LHB in the Golgi apparatus; the functional domain required for HBV inhibition is distinct from that required for HIV-1 restriction. Overexpression/knockdown infectivity assays, glycoprotein glycosylation analysis, confocal co-localization (Golgi), domain deletion mutagenesis Frontiers in microbiology Medium 32431673
2020 SERINC5 inhibits HIV-1 infectivity by altering the conformation of gp120 on HIV-1 virions; virions with SERINC5-susceptible Env showed reduced binding to V3-loop, sCD4-induced, and N-linked glycan epitope antibodies, while SERINC5-resistant Env was unaffected; this conformational effect was abrogated by Nef. Virion capture assay with panel of Env-specific monoclonal antibodies, SERINC5-susceptible vs. resistant Env comparison Journal of virology Medium 32796070
2021 SERINC5 interacts with MDA5 (melanoma differentiation-associated protein 5) as shown by yeast two-hybrid, co-localization, and co-immunoprecipitation; SERINC5 enhances MDA5-mediated type I interferon signaling in a dose-dependent manner; silencing MDA5 abolishes the anti-CSFV effect of SERINC5, indicating SERINC5 exerts anti-CSFV activity in an MDA5-dependent manner. Yeast two-hybrid, co-immunoprecipitation, co-localization, MDA5 siRNA knockdown, type I IFN reporter assay Frontiers in microbiology Medium 33013817
2021 SERINC5 virion incorporation potentiates proinflammatory cytokine production by monocyte-derived macrophages and dendritic cells in response to HIV-1 particles; this effect is Nef-sensitive, requires HIV-1 Env-mediated (not VSV-G) entry, and can be reproduced by inhibiting entry of SERINC5-negative HIV-1 ΔNef particles. Primary human macrophage/dendritic cell infection, cytokine ELISA, VSV-G vs. HIV-1 Env pseudotyping, Nef rescue, entry inhibition Journal of virology Medium 33597208
2021 An aromatic side chain (phenylalanine, tyrosine, or tryptophan) at position 412 of SERINC5 is required for its restriction function against diverse retroviruses; the F412A substitution abolishes restriction and sensitization of HIV-1 neutralization by antibodies targeting the membrane proximal region, while maintaining plasma membrane localization and virion incorporation. Systematic mutagenesis at F412, infectivity assays with multiple retroviral Envs, neutralization assays, cell surface flow cytometry, virion incorporation Western blot Journal of virology Medium 34190600
2024 SERINC5 inhibits HIV-1 transcription by negatively regulating NF-κB signaling; SERINC5 recruits TRIM40 as an E3 ubiquitin ligase to promote K48-linked polyubiquitination and proteasomal degradation of MDA5 and RIG-I, impeding nuclear translocation of p50/p65 and repressing HIV-1 LTR-driven gene expression. HIV-1 LTR reporter assay, co-immunoprecipitation (TRIM40-MDA5/RIG-I), ubiquitination assay (K48-linkage), nuclear fractionation (p50/p65), TRIM40 knockdown/overexpression The Journal of biological chemistry Medium 39653243
2024 Serinc5 is specifically expressed in pre-hypertrophic chondrocytes of the growth plate; Serinc5 represses chondrocyte proliferation and Col2a1/Acan expression by inhibiting the transcriptional activity of Sox9; ChIP-seq and ATAC-seq identified an active enhancer in intron 1 with chromatin progressively opened during chondrocyte differentiation. scRNA-seq, histological analysis, ChIP-seq, ATAC-seq, Sox9 transcriptional activity reporter assay in primary chondrocytes, gain/loss-of-function Journal of cellular physiology Medium 39568258
2025 MLV glycoGag antagonizes SERINC5 via two mechanisms: (1) at the cell surface via the endolysosomal pathway (similar to Nef), and (2) at the ER via reticulophagy regulator 1 (RETREG1)-dependent micro-ER-phagy, an autophagosome-independent process; glycoGag binds SERINC5 in the ER, recruits RETREG1, and degrades ER-retained SERINC5 through a pathway that bypasses ATG3/5/7, BECN1, LC3 lipidation, and PIK3C3. CRISPR/Cas9 knockouts of RETREG1 and autophagy genes, co-immunoprecipitation, subcellular fractionation, K130R ER-retention mutant, affinity purification/mass spectrometry PLoS pathogens High 41066524
2025 SERINC5 expressed in target cells (not only in virion-producing cells) can inhibit HIV-1 Env-mediated cell-cell fusion by destabilizing small fusion pores and causing their collapse; this effect is rescued by incorporation of phosphatidylserine into the membrane of either effector or target cells; SERINC5 in target cells does not reduce CD4 or co-receptor levels nor interfere with Env/CD4/co-receptor ternary complex formation. Cell-cell fusion assay (fusion-from-without), single-particle pseudovirus fusion assay, receptor flow cytometry, phosphatidylserine rescue, lipid mixing assay mBio Medium 41247072
2025 A tri-cysteine motif (Cys355, Cys356, Cys358) within intracellular loop 4 (ICL4) of SERINC5 is required for Nef-mediated downregulation; substitution of these cysteines with glutamines confers resistance to HIV-1 and SIV Nef alleles but not to MLV glycoGag or EIAV S2, indicating Nef exploits a distinct structural feature of SERINC5; SERINC5 is palmitoylated at this tri-cysteine motif. Structure-guided mutagenesis, Nef-mediated downregulation assay, virion exclusion assay, palmitoylation assay, cross-species Nef panel bioRxivpreprint Medium bio_10.1101_2025.10.27.684794
2025 Nef recruits SERINC3 via binding to its N-terminal cytosolic tail; Nef residues important for SERINC3 binding in vitro and for exclusion of SERINC3 from virions overlap with those required for Nef-mediated CD4 downregulation, using the conserved substrate-binding pocket of Nef. In vitro binding assay, Nef mutagenesis, virion exclusion assay, structural mapping of Nef substrate-binding pocket bioRxivpreprint Medium bio_10.1101_2025.04.12.648528

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. Nature 381 26416733
2015 HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. Nature 367 26416734
2017 SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins. The Journal of biological chemistry 113 28179429
2017 Effect of HIV-1 Env on SERINC5 Antagonism. Journal of virology 88 27928004
2018 HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System. Journal of virology 81 29514909
2016 The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild. Cell host & microbe 81 27631701
2016 S2 from equine infectious anemia virus is an infectivity factor which counteracts the retroviral inhibitors SERINC5 and SERINC3. Proceedings of the National Academy of Sciences of the United States of America 78 27803322
2017 The host-cell restriction factor SERINC5 restricts HIV-1 infectivity without altering the lipid composition and organization of viral particles. The Journal of biological chemistry 67 28659343
2002 Saccharomyces cerevisiae resistance to chlorinated phenoxyacetic acid herbicides involves Pdr1p-mediated transcriptional activation of TPO1 and PDR5 genes. Biochemical and biophysical research communications 65 11906193
2005 Characteristics of the polyamine transporter TPO1 and regulation of its activity and cellular localization by phosphorylation. The Journal of biological chemistry 60 15637075
2016 Functional Interplay Between Murine Leukemia Virus Glycogag, Serinc5, and Surface Glycoprotein Governs Virus Entry, with Opposite Effects on Gammaretroviral and Ebolavirus Glycoproteins. mBio 54 27879338
2016 The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor. Journal of virology 53 27681140
2022 SARS-CoV-2 ORF7a potently inhibits the antiviral effect of the host factor SERINC5. Nature communications 49 35618710
2001 Novel target genes of the yeast regulator Pdr1p: a contribution of the TPO1 gene in resistance to quinidine and other drugs. Gene 46 11470516
2017 Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction. Journal of virology 44 28275190
2017 Localization to detergent-resistant membranes and HIV-1 core entry inhibition correlate with HIV-1 restriction by SERINC5. Virology 44 29268082
2018 A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef. Cell reports 42 29386131
2019 CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5. Journal of virology 41 31043528
2019 The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5. The Journal of biological chemistry 39 30862674
2018 An N-Glycosylated Form of SERINC5 Is Specifically Incorporated into HIV-1 Virions. Journal of virology 32 30158294
2016 The Evolutionary Histories of Antiretroviral Proteins SERINC3 and SERINC5 Do Not Support an Evolutionary Arms Race in Primates. Journal of virology 32 27356902
2006 Adaptive response to the antimalarial drug artesunate in yeast involves Pdr1p/Pdr3p-mediated transcriptional activation of the resistance determinants TPO1 and PDR5. FEMS yeast research 31 17156010
2020 SERINC5 Potently Restricts Retrovirus Infection In Vivo. mBio 27 32665269
2019 Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5. mBio 26 31186327
1997 TPO1, a member of a novel protein family, is developmentally regulated in cultured oligodendrocytes. Journal of neurochemistry 25 9326262
2020 Flow Cytometry Analysis of HIV-1 Env Conformations at the Surface of Infected Cells and Virions: Role of Nef, CD4, and SERINC5. Journal of virology 24 31852789
2021 Influence of Different Glycoproteins and of the Virion Core on SERINC5 Antiviral Activity. Viruses 23 34209034
2020 SERINC5 Inhibits HIV-1 Infectivity by Altering the Conformation of gp120 on HIV-1 Particles. Journal of virology 23 32796070
2020 SERINC5 Inhibits the Secretion of Complete and Genome-Free Hepatitis B Virions Through Interfering With the Glycosylation of the HBV Envelope. Frontiers in microbiology 22 32431673
2019 Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor. Journal of virology 22 31597782
2020 Nef homodimers down-regulate SERINC5 by AP-2-mediated endocytosis to promote HIV-1 infectivity. The Journal of biological chemistry 21 32873704
2018 SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue. PLoS pathogens 21 30125328
2023 Serinc5 Restricts HIV Membrane Fusion by Altering Lipid Order and Heterogeneity in the Viral Membrane. ACS infectious diseases 20 36946615
2020 A Conserved Acidic-Cluster Motif in SERINC5 Confers Partial Resistance to Antagonism by HIV-1 Nef. Journal of virology 20 31941773
2007 Identification of the TPO1 gene in yeast, and its human orthologue TETRAN, which cause resistance to NSAIDs. FEBS letters 18 17362938
2022 Cul3-KLHL20 E3 ubiquitin ligase plays a key role in the arms race between HIV-1 Nef and host SERINC5 restriction. Nature communications 17 35474067
2020 Differential Pressures of SERINC5 and IFITM3 on HIV-1 Envelope Glycoprotein over the Course of HIV-1 Infection. Journal of virology 17 32493821
2022 SERINC5 restricts influenza virus infectivity. PLoS pathogens 16 36223419
2020 SERINC5 Is an Unconventional HIV Restriction Factor That Is Upregulated during Myeloid Cell Differentiation. Journal of innate immunity 16 31935717
2022 Restriction of Influenza A Virus by SERINC5. mBio 15 36409124
2021 SERINC5 Can Enhance Proinflammatory Cytokine Production by Primary Human Myeloid Cells in Response to Challenge with HIV-1 Particles. Journal of virology 14 33597208
2021 Nef Obtained from Individuals with HIV-1 Vary in Their Ability to Antagonize SERINC3- and SERINC5-Mediated HIV-1 Restriction. Viruses 14 33800773
2021 HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity. Cell reports 14 34380030
2020 Antiviral Role of Serine Incorporator 5 (SERINC5) Proteins in Classical Swine Fever Virus Infection. Frontiers in microbiology 14 33013817
2015 Spotlight on HIV-1 Nef: SERINC3 and SERINC5 Identified as Restriction Factors Antagonized by the Pathogenesis Factor. Viruses 13 26703715
2022 SERINC5 Restricts HIV-1 Infectivity by Promoting Conformational Changes and Accelerating Functional Inactivation of Env. Viruses 12 35891369
2018 The antiviral activity of rodent and lagomorph SERINC3 and SERINC5 is counteracted by known viral antagonists. The Journal of general virology 12 30566072
2021 An Amino Acid Polymorphism within the HIV-1 Nef Dileucine Motif Functionally Uncouples Cell Surface CD4 and SERINC5 Downregulation. Journal of virology 11 34037423
2020 Longitudinal within-host evolution of HIV Nef-mediated CD4, HLA and SERINC5 downregulation activity: a case study. Retrovirology 11 31918727
2020 Impaired ability of Nef to counteract SERINC5 is associated with reduced plasma viremia in HIV-infected individuals. Scientific reports 11 33173092
2022 HIV-1 restriction by SERINC5. Medical microbiology and immunology 10 35333966
2022 Nef enhances HIV-1 replication and infectivity independently of SERINC5 in CEM T cells. Virology 9 36577173
2017 Yeast response and tolerance to benzoic acid involves the Gcn4- and Stp1-regulated multidrug/multixenobiotic resistance transporter Tpo1. Applied microbiology and biotechnology 8 28409382
2022 Interaction of SERINC5 and IFITM1/2/3 regulates the autophagy-apoptosis-immune network under CSFV infection. Virulence 7 36205528
2003 Cloning and expression of a novel human C5orf12 gene*, a member of the TMS_TDE family. Molecular biology reports 7 12688535
2023 AP-2 Adaptor Complex-Dependent Enhancement of HIV-1 Replication by Nef in the Absence of the Nef/AP-2 Targets SERINC5 and CD4. mBio 6 36622146
2023 SARS-CoV-2-encoded small RNAs are able to repress the host expression of SERINC5 to facilitate viral replication. Frontiers in microbiology 6 36876111
2023 A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation. Viruses 6 36992361
2023 The Antiviral Factor SERINC5 Impairs the Expression of Non-Self-DNA. Viruses 6 37766367
2022 SERINC5-Mediated Restriction of HIV-1 Infectivity Correlates with Resistance to Cholesterol Extraction but Not with Lipid Order of Viral Membrane. Viruses 6 35893701
2021 Selective Disruption of SERINC5 Antagonism by Nef Impairs SIV Replication in Primary CD4+ T Cells. Journal of virology 6 33504599
2021 Aromatic Side Chain at Position 412 of SERINC5 Exerts Restriction Activity toward HIV-1 and Other Retroviruses. Journal of virology 6 34190600
2014 Upregulation of the Saccharomyces cerevisiae efflux pump Tpo1 rescues an Imp2 transcription factor-deficient mutant from bleomycin toxicity. Environmental and molecular mutagenesis 6 24599794
2006 Identification and functional characterization of mouse TPO1 as a myelin membrane protein. Brain research 6 16405874
2024 Serinc5 Regulates Sequential Chondrocyte Differentiation by Inhibiting Sox9 Function in Pre-Hypertrophic Chondrocytes. Journal of cellular physiology 5 39568258
2023 HIV-1 subtype C Nef-mediated SERINC5 down-regulation significantly contributes to overall Nef activity. Retrovirology 5 37004071
2023 Relative resistance of patient-derived envelope sequences to SERINC5-mediated restriction of HIV-1 infectivity. Journal of virology 5 37768085
2025 Murine leukemia virus glycoGag antagonizes SERINC5 via ER-phagy receptor RETREG1. PLoS pathogens 4 41066524
2024 Beyond Impairment of Virion Infectivity: New Activities of the Anti-HIV Host Cell Factor SERINC5. Viruses 4 38400059
2021 Feline Leukemia Virus-B Envelope Together With its GlycoGag and Human Immunodeficiency Virus-1 Nef Mediate Resistance to Feline SERINC5. Journal of molecular biology 4 34954236
2021 Downregulation of SERINC5 expression in buffy coats of HIV-1-infected patients with detectable or undetectable viral load. Molecular biology reports 3 34097204
2020 Sensitivity to monoclonal antibody 447-52D and an open env trimer conformation correlate poorly with inhibition of HIV-1 infectivity by SERINC5. Virology 3 32838948
2025 HIV-1 and BLV are insensitive to SERINC5 restriction under the cell-cell infection. Microbiology spectrum 2 39868869
2025 SERINC5 counters retroviruses and non-retroviruses. Frontiers in cellular and infection microbiology 2 39902183
2022 Substitutions in Nef That Uncouple Tetherin and SERINC5 Antagonism Impair Simian Immunodeficiency Virus Replication in Primary Rhesus Macaque Lymphocytes. Journal of virology 2 35536019
2020 Novel monoclonal antibodies to the SERINC5 HIV-1 restriction factor detect endogenous andvirion-associated SERINC5. mAbs 2 32835602
2025 Murine Leukemia Virus GlycoGag Antagonizes SERINC5 via ER-phagy Receptor RETREG1. bioRxiv : the preprint server for biology 1 40093084
2025 RETREG1/FAM134B-mediated micro-ER-phagy in the retrovirus-SERINC5 arms race. Autophagy reports 1 41438769
2024 Functional variability of Nef in antagonizing SERINC5 during acute to chronic HIV-1 infection. AIDS (London, England) 1 39612239
2024 The host restriction factor SERINC5 inhibits HIV-1 transcription by negatively regulating NF-κB signaling. The Journal of biological chemistry 1 39653243
2026 Human Coronavirus 229E Uses ORF4/4a to Antagonize the Host Restriction Factor SERINC5. MedComm 0 42253925
2025 SERINC5 co-expressed with HIV-1 Env or present in a target membrane destabilizes small fusion pores leading to their collapse. bioRxiv : the preprint server for biology 0 40964405
2025 SERINC5 co-expressed with HIV-1 Env or present in a target membrane destabilizes small fusion pores leading to their collapse. mBio 0 41247072
2025 TPO1-based polyamines transport contributes to pathogenicity of sugarcane smut fungus. Mycology 0 41878515

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