SERINC1 is a 453-residue, N-myristoylated multipass membrane protein of the conserved SERINC family. At the endoplasmic-reticulum membrane it is implicated in organizing and stimulating enzymes that incorporate serine into phosphatidylserine and sphingolipids, thereby supporting membrane-lipid biogenesis. This activity is established directly for rat Serinc1 and transferred to the human ortholog; endogenous human biochemical activity has not yet been demonstrated. Serinc1 loss in mouse macrophages and lymphocytes does not alter serine-derived lipid composition or the tested immune-cell functions, indicating substantial context dependence or compensation by other SERINC proteins.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: The phylogenetic annotation correctly places SERINC1 in a membrane but is less specific than the experimentally supported ER-membrane location. Reason: Rat Serinc1 co-localizes with lipid-biosynthetic enzymes in ER membranes, and reviewed human UniProt transfers that location to Q9NRX5. Endoplasmic reticulum membrane is therefore the informative functional location. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:16120614 rat Serinc1 protein co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SERINC1 is an integral multipass protein of the endoplasmic-reticulum membrane. Reason: Reviewed human UniProt and direct localization of rat Serinc1 both support the ER membrane, which is also the site of the lipid-biosynthetic machinery affected by SERINC1. Supporting Evidence: file:human/SERINC1/SERINC1-uniprot.txt Endoplasmic reticulum membrane PMID:16120614 rat Serinc1 protein co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro mapping correctly recognizes SERINC1 as a membrane protein but is too broad. Reason: Eleven predicted transmembrane helices support membrane integration, while orthology and experimental evidence identify the ER membrane as the specific principal location. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/SERINC1/SERINC1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | MARK AS OVER ANNOTATED | Summary: A systematic mRNA-display screen reports a candidate interaction between SERINC1 and PAX8. Reason: The high-throughput interaction does not establish a SERINC1-specific molecular activity or connect PAX8 binding to serine-derived lipid synthesis. Generic protein binding is uninformative compared with the adaptor and enzyme-regulator functions. Supporting Evidence: PMID:20195357 Large-scale data sets of protein-protein interactions (PPIs) are a valuable |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: HuRI reports candidate binary interactions of SERINC1 with FFAR3, GPR42, AQP9, and GPX8. Reason: These systematic yeast-two-hybrid contacts have no demonstrated functional consequence for SERINC1. Retaining generic protein binding would obscure the informative lipid-biogenesis adaptor and enzyme-activator roles. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0010698 acetyltransferase activator activity | ISS GO_REF:0000024 | MODIFY | Summary: Mammalian Serinc1 stimulates lipid-biosynthetic enzyme activities, but acetyltransferase activator is the wrong enzyme-class specificity. Reason: The experiments concern phosphatidylserine synthase and serine C-palmitoyltransferase. The latter is an acyltransferase rather than an acetyltransferase, so the broader enzyme activator activity accurately retains the demonstrated essence without assigning an unsupported enzyme subclass. Proposed replacements: enzyme activator activity Supporting Evidence: PMID:16120614 facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. file:human/SERINC1/SERINC1-deep-research-manual.md serine C-palmitoyltransferase is an acyltransferase, |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: SERINC1 is an integral multipass protein of the endoplasmic-reticulum membrane. Reason: Reviewed human UniProt and direct localization of rat Serinc1 both support the ER membrane, which is also the site of the lipid-biosynthetic machinery affected by SERINC1. Supporting Evidence: file:human/SERINC1/SERINC1-uniprot.txt Endoplasmic reticulum membrane PMID:16120614 rat Serinc1 protein co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes. |
| GO:0030674 protein-macromolecule adaptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: SERINC1 is proposed to organize serine-synthetic and lipid-biosynthetic enzymes at the ER membrane. Reason: Rat Serinc1 interacts with SPTLC1, and the family-level study describes a membrane complex linking serine synthesis to incorporation into phosphatidylserine and sphingolipids. The highly conserved human ortholog is a defensible ISS transfer. Supporting Evidence: PMID:16120614 A Serinc protein forms an intracellular complex with key enzymes involved in serine and sphingolipid biosyntheses |
| GO:0044091 membrane biogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: SERINC1 promotes production of serine-derived membrane lipids. Reason: Increased incorporation of serine into phosphatidylserine and sphingolipids directly links mammalian Serinc proteins to formation of major membrane-lipid classes. The broad membrane-biogenesis process appropriately integrates those outputs. Supporting Evidence: PMID:16120614 facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | UNDECIDED | Summary: Plasma-membrane localization was transferred from a rat experimental annotation, but the accessible evidence emphasizes the ER membrane. Reason: The rat curator had access to full experimental context, whereas the local PMID cache is abstract-only and reviewed human UniProt lists only the ER membrane. The plasma-membrane assertion cannot be confidently confirmed or rejected from the available evidence. Supporting Evidence: PMID:16120614 rat Serinc1 protein co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes. file:human/SERINC1/SERINC1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006658 phosphatidylserine metabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Mammalian Serinc1 enhances incorporation of serine into phosphatidylserine. Reason: Rat Serinc1 expression increases phosphatidylserine synthesis, and the conserved human ortholog carries the same reviewed functional statement. The mouse knockout result indicates redundancy in immune cells but does not contradict pathway participation. Supporting Evidence: PMID:16120614 facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. PMID:28006656 did not significantly alter serine-derived lipid composition |
| GO:0006665 sphingolipid metabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Mammalian Serinc1 enhances serine incorporation into sphingolipids. Reason: Rat Serinc1 expression and complementation experiments support increased serine-palmitoyltransferase output and sphingolipid synthesis. Conservation supports transfer to human, while the negative single-knockout immune-cell phenotype suggests buffering rather than absence of function. Supporting Evidence: PMID:16120614 facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. PMID:28006656 did not significantly alter serine-derived lipid composition |
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Download this section (compressed HTML)Q: Does endogenous human SERINC1 directly organize serine-synthetic enzymes with phosphatidylserine synthase and serine palmitoyltransferase at the ER membrane?
Q: Which other SERINC paralogs compensate for SERINC1 loss, and is compensation cell-type or metabolic-state dependent?
Q: Does human SERINC1 have a bona fide plasma-membrane pool, and if so, what molecular activity occurs there?
Experiment: Generate SERINC1-null human cells, restore untagged SERINC1 at endogenous abundance, and combine stable-isotope serine tracing with quantitative phosphatidylserine and sphingolipid lipidomics, direct enzyme assays, and endogenous co-complex measurements.
Hypothesis: Human SERINC1 promotes serine-derived lipid synthesis through an ER-localized adaptor/enzyme-activator mechanism.
Type: Endogenous knockout-rescue with isotope-resolved lipid biochemistry
Experiment: Construct single and combinatorial SERINC knockouts in immune and neuronal human cell models, quantify paralog expression and serine-derived lipids, and perform paralog-specific rescue under basal and lipid-demanding conditions.
Hypothesis: Other SERINC-family proteins compensate for SERINC1 loss in a cell-type-dependent manner.
Type: Combinatorial genetic epistasis and lipidomics
Experiment: Endogenously tag SERINC1 and compare surface labeling, live-cell imaging, glycan maturation, and ER/plasma-membrane fractionation with lipid-synthesis readouts and localization-defective mutants.
Hypothesis: SERINC1 is predominantly ER-resident, while any plasma-membrane pool is regulated and functionally distinct.
Type: Endogenous localization and separation-of-function analysis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Direct endogenous human evidence for SERINC1 adaptor and enzyme-activator activity is lacking.
OPEN BIOLOGY MF_DARK
What is known: The core biochemical experiments used rat Serinc1, yeast Tms1 complementation, and heterologous expression; reviewed human function is assigned by orthology.
Significance: Direct human validation is needed to distinguish a conserved SERINC1 mechanism from family-level redundancy or context-specific activity.
What would resolve it: Delete endogenous SERINC1 in human cells, rescue with Q9NRX5 at matched abundance, and measure isotope-resolved serine incorporation, phosphatidylserine-synthase and serine-palmitoyltransferase activities, and endogenous complex assembly.
Provenance (the field's own admissions):
Gap: The extent of functional redundancy among human SERINC paralogs is unresolved.
OPEN BIOLOGY BP_DARK
What is known: A mouse Serinc1 single-gene knockout showed no immune-cell lipid or functional phenotype despite the overexpression biochemistry.
Significance: Compensation could mask an essential shared role in serine-derived lipid synthesis and explains why single-gene loss is silent in some cell types.
What would resolve it: Compare single and combinatorial SERINC knockouts across human cell types using quantitative lipidomics, isotope tracing, and paralog-specific rescue.
Provenance (the field's own admissions):
Gap: Whether endogenous human SERINC1 has a functional plasma-membrane pool is uncertain.
OPEN BIOLOGY CC_DARK
What is known: The source rat GO record contains a plasma-membrane IDA annotation, while the accessible paper abstract and reviewed human UniProt emphasize the ER membrane.
Significance: Resolving location is necessary to determine where SERINC1 acts and whether it has functions distinct from ER lipid synthesis.
What would resolve it: Use endogenous epitope tagging, selective surface labeling, quantitative imaging, and organelle fractionation with topology controls in several human cell types.
Provenance (the field's own admissions):
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