NOSIP

gene
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Also known as CGI-25

Summary

NOSIP (nitric oxide synthase interacting protein, HGNC:17946) is a protein-coding gene on chromosome 19q13.33, encoding Nitric oxide synthase-interacting protein (Q9Y314). E3 ubiquitin-protein ligase that is essential for proper development of the forebrain, the eye, and the face.

The protein encoded by this gene may modulate the activity and localization of nitric oxide synthase (endothelial and neuronal) and thus nitric oxide production. Alternative splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 51070 — RefSeq curated summary.

At a glance

  • GWAS associations: 7
  • Clinical variants (ClinVar): 53 total
  • Druggable target: yes
  • MANE Select transcript: NM_001270960

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:17946
Approved symbolNOSIP
Namenitric oxide synthase interacting protein
Location19q13.33
Locus typegene with protein product
StatusApproved
AliasesCGI-25
Ensembl geneENSG00000142546
Ensembl biotypeprotein_coding
OMIM616759
Entrez51070

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 25 protein_coding, 8 retained_intron, 2 nonsense_mediated_decay, 1 non_stop_decay

ENST00000339093, ENST00000593345, ENST00000594932, ENST00000596358, ENST00000596477, ENST00000598296, ENST00000598544, ENST00000598550, ENST00000598820, ENST00000598839, ENST00000599425, ENST00000599537, ENST00000600019, ENST00000601015, ENST00000601107, ENST00000601340, ENST00000874162, ENST00000874163, ENST00000874164, ENST00000874165, ENST00000874166, ENST00000874167, ENST00000874168, ENST00000874169, ENST00000874170, ENST00000874171, ENST00000874172, ENST00000874173, ENST00000874174, ENST00000917073, ENST00000917074, ENST00000917075, ENST00000917076, ENST00000917077, ENST00000962184, ENST00000962185

RefSeq mRNA: 3 — MANE Select: NM_001270960 NM_001270960, NM_001363649, NM_015953

CCDS: CCDS12772, CCDS86789

Canonical transcript exons

ENST00000596358 — 9 exons

ExonStartEnd
ENSE000013778174958051549580556
ENSE000034980904956062249560692
ENSE000034995544955993449560039
ENSE000035117094955687549556993
ENSE000035628664955889749558978
ENSE000035684804955709049557249
ENSE000036310834955631749556425
ENSE000037915374955654949556736
ENSE000038961924955546849555822

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.5923 / max 600.7309, expressed in 1824 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter IDTPM avgSamples expressed
18205737.22941823
1820542.449494
1820582.41261446
1820531.2812727
1820480.5428133
1820490.505677
1820500.352761
1820520.321799
1820550.242264
1820560.169866

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
left testisUBERON:000453397.99gold quality
granulocyteCL:000009497.96gold quality
right testisUBERON:000453497.85gold quality
body of pancreasUBERON:000115096.87gold quality
triceps brachiiUBERON:000150996.77gold quality
hindlimb stylopod muscleUBERON:000425296.71gold quality
bloodUBERON:000017896.63gold quality
mucosa of transverse colonUBERON:000499196.43gold quality
tendon of biceps brachiiUBERON:000818896.19gold quality
testisUBERON:000047396.17gold quality
gluteal muscleUBERON:000200095.86gold quality
gastrocnemiusUBERON:000138895.60gold quality
muscle of legUBERON:000138395.57gold quality
male germ cellCL:000001595.37gold quality
spermCL:000001995.32gold quality
muscle organUBERON:000163095.28gold quality
vastus lateralisUBERON:000137995.08gold quality
apex of heartUBERON:000209894.99gold quality
lymph nodeUBERON:000002994.97gold quality
pancreasUBERON:000126494.95gold quality
quadriceps femorisUBERON:000137794.74gold quality
spleenUBERON:000210694.62gold quality
lower esophagus mucosaUBERON:003583494.29gold quality
skeletal muscle tissue of rectus abdominisUBERON:000451194.26gold quality
ectocervixUBERON:001224994.15gold quality
endocervixUBERON:000045894.14gold quality
amniotic fluidUBERON:000017394.12gold quality
right atrium auricular regionUBERON:000663194.10gold quality
skeletal muscle tissueUBERON:000113494.09gold quality
transverse colonUBERON:000115794.09gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 7.

ExperimentMarker?Max mean expression
E-HCAD-4yes736.71
E-MTAB-8911yes474.91
E-CURD-122yes102.42
E-CURD-88yes57.78
E-HCAD-1yes30.54
E-CURD-112yes9.27
E-MTAB-7606no2754.76
E-CURD-55no815.18
E-CURD-77no718.63
E-CURD-85no550.35
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting NOSIP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-4677-5P99.7070.091940
HSA-MIR-2116-5P99.3269.341273
HSA-MIR-6739-3P99.2268.841843

Literature-anchored findings (GeneRIF, showing 5)

  • endothelial nitric oxide synthase (eNOS) interacting protein (NOSIP), modulator of eNOS activity by alteration of eNOS subcellular localisation; high expression levels in endothelial cells and vascularized tissue. (PMID:11149895)
  • Endogenous NOSIP reduces the enzymatic capacity of eNOS, specifically in the G(2) phase of the cell cycle by targeting eNOS to the actin cytoskeleton. (PMID:16135813)
  • While NOSIP expression was increased in Hirschsprung’s disease (HSCR) vs. non- HSCR patients, no significant difference was observed in patients with Hirschsprung’s associated enterocolitis. The increased expression of NOSIP in the aganglionic and ganglionic bowel of HSCR may contribute to the development of enterocolitis by inhibiting local nitric oxide production in patients with Hirschsprung’s disease. (PMID:28196663)
  • nNOS induction and NOSIP interaction impact granulopoiesis and neutrophil differentiation by modulating nitric oxide generation. (PMID:33771575)
  • Transportin 1 is a major nuclear import receptor of the nitric oxide synthase interacting protein. (PMID:36690276)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_rerionosipENSDARG00000037958
mus_musculusNosipENSMUSG00000003421
rattus_norvegicusNosipENSRNOG00000020543
drosophila_melanogasterCG6179FBGN0030915
caenorhabditis_elegansWBGENE00019898

Protein

Protein identifiers

Nitric oxide synthase-interacting proteinQ9Y314 (reviewed: Q9Y314)

Alternative names: E3 ubiquitin-protein ligase NOSIP, RING-type E3 ubiquitin transferase NOSIP, eNOS-interacting protein

All UniProt accessions (7): Q9Y314, A0A075B6F9, A0A075B797, M0QX85, M0R1K2, M0R1T7, M0R3B2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that is essential for proper development of the forebrain, the eye, and the face. Catalyzes monoubiquitination of serine/threonine-protein phosphatase 2A (PP2A) catalytic subunit PPP2CA/PPP2CB. Negatively regulates nitric oxide production by inducing NOS1 and NOS3 translocation to actin cytoskeleton and inhibiting their enzymatic activity.

Subunit / interactions. Interacts with NOS1 and NOS3. Interacts with PP2A holoenzyme, containing PPP2CA, PPP2CB, PPP2R1A and PPP2R2A subunits.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in heart, brain and lung. Present in endothelial cells (at protein level).

Domain organisation. The U-box-like region is a truncated U-box domain. It is unknown whether it is functional or not.

Similarity. Belongs to the NOSIP family.

RefSeq proteins (3): NP_001257889, NP_001350578, NP_057037 (=MANE)

Domains & families (InterPro)

IDNameType
IPR013083Znf_RING/FYVE/PHDHomologous_superfamily
IPR016818NOSIPFamily
IPR031790Znf-NOSIPDomain

Pfam: PF15906

UniProt features (7 total): region of interest 2, modified residue 2, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDBMethodResolution (Å)
8C6JELECTRON MICROSCOPY2.8
9FMDELECTRON MICROSCOPY3.3

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9Y314-F182.040.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 36, 107

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-203754NOSIP mediated eNOS trafficking

MSigDB gene sets: 206 (showing top): AREB6_01, GOBP_REGULATION_OF_OXIDOREDUCTASE_ACTIVITY, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_NITRIC_OXIDE_SYNTHASE_ACTIVITY, GOBP_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_OXIDOREDUCTASE_ACTIVITY, BLALOCK_ALZHEIMERS_DISEASE_UP, JAZAG_TGFB1_SIGNALING_VIA_SMAD4_UP, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, HP1SITEFACTOR_Q6, GOBP_NEGATIVE_REGULATION_OF_CATALYTIC_ACTIVITY, LIU_CMYB_TARGETS_UP, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, CETS1P54_01, OSMAN_BLADDER_CANCER_DN

GO Biological Process (5): negative regulation of catalytic activity (GO:0043086), regulation of nitric oxide biosynthetic process (GO:0045428), nitric oxide metabolic process (GO:0046209), negative regulation of nitric-oxide synthase activity (GO:0051001), protein ubiquitination (GO:0016567)

GO Molecular Function (6): RNA binding (GO:0003723), ubiquitin protein ligase activity (GO:0061630), molecular sequestering activity (GO:0140313), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (5): Golgi membrane (GO:0000139), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Metabolism of nitric oxide: NOS3 activation and regulation1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure3
catalytic activity2
negative regulation of molecular function1
regulation of catalytic activity1
nitric oxide biosynthetic process1
regulation of biosynthetic process1
regulation of nitric oxide metabolic process1
reactive nitrogen species metabolic process1
nitric-oxide synthase activity1
regulation of nitric-oxide synthase activity1
negative regulation of oxidoreductase activity1
protein modification by small protein conjugation1
nucleic acid binding1
ubiquitin-protein transferase activity1
ubiquitin-like protein ligase activity1
molecular_function1
ubiquitin-like protein transferase activity1
binding1
Golgi apparatus1
bounding membrane of organelle1
intracellular membrane-bounded organelle1
nuclear lumen1
intracellular anatomical structure1
cytoplasm1

Protein interactions and networks

STRING

962 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
NOSIPNOS3P29474961
NOSIPNOSTRINQ8IVI9675
NOSIPCAV1Q03135627
NOSIPNOS1P29475538
NOSIPPRRG2O14669523
NOSIPDNM2P50570523
NOSIPHSP90AA1P07900521
NOSIPHSP90AB1P08238520
NOSIPPRKG1P14619509
NOSIPC9orf78Q9NZ63455
NOSIPRCN3Q96D15452
NOSIPNOS1APO75052442
NOSIPERBB2P04626402
NOSIPRPL13AP40429396
NOSIPFAM20CQ8IXL6395

IntAct

32 interactions, top by confidence:

ABTypeScore
ZNF410NOSIPpsi-mi:“MI:0915”(physical association)0.560
NOSIPTNNC2psi-mi:“MI:0914”(association)0.530
OTUB1psi-mi:“MI:0914”(association)0.350
OTUB1EPM2Apsi-mi:“MI:0914”(association)0.350
JUNpsi-mi:“MI:0914”(association)0.350
JUNTPM3psi-mi:“MI:0914”(association)0.350
HSCBRBP5psi-mi:“MI:0914”(association)0.350
RRP1BZNF785psi-mi:“MI:0914”(association)0.350
CUL3PXDNLpsi-mi:“MI:0914”(association)0.350
POLLSULT1C2psi-mi:“MI:0914”(association)0.350
NEU2PEX14psi-mi:“MI:0914”(association)0.350
RASGRF2SNRPApsi-mi:“MI:0914”(association)0.350
CEP135MCRIP1psi-mi:“MI:0914”(association)0.350
CEP135WWP2psi-mi:“MI:0914”(association)0.350
CEP135WDR91psi-mi:“MI:0914”(association)0.350
CAPZBENAHpsi-mi:“MI:0914”(association)0.350
S100PPLEKHG3psi-mi:“MI:0914”(association)0.350
HAP1PPP1R12Apsi-mi:“MI:0914”(association)0.350
LMNASMCHD1psi-mi:“MI:2364”(proximity)0.270
TP53BP1PSMD14psi-mi:“MI:2364”(proximity)0.270
KLF16SMCHD1psi-mi:“MI:2364”(proximity)0.270
HNRNPCSBNO1psi-mi:“MI:2364”(proximity)0.270
PPIL4ESYT2psi-mi:“MI:2364”(proximity)0.270
ZRANB2SBNO1psi-mi:“MI:2364”(proximity)0.270
NPM1SBNO1psi-mi:“MI:2364”(proximity)0.270
NOSIPBCAR3psi-mi:“MI:0915”(physical association)0.000

BioGRID (136): NOSIP (Affinity Capture-MS), NOSIP (Affinity Capture-MS), NOSIP (Affinity Capture-MS), TNNC2 (Affinity Capture-MS), NOSIP (Affinity Capture-MS), HMCES (Co-fractionation), NOSIP (Co-fractionation), NOSIP (Co-fractionation), NOSIP (Co-fractionation), NOSIP (Affinity Capture-MS), NOSIP (Affinity Capture-MS), NOSIP (Affinity Capture-MS), PPP2CA (Affinity Capture-MS), PPP2CB (Affinity Capture-MS), PPP2R1A (Affinity Capture-MS)

ESM2 similar proteins: A6SGN8, A7EWN6, B4I9X1, B4NTY9, O43395, O60869, O60870, O64981, O70333, P10871, P10896, P31753, P93431, Q1WCC0, Q2KIA6, Q32LC9, Q3SWY5, Q3T0V7, Q3ZC66, Q40073, Q4R7H4, Q567Z6, Q5R5F1, Q5U5C5, Q5ZJ85, Q5ZKB6, Q5ZMC0, Q6F444, Q6FJN0, Q6NU28, Q6NVP6, Q6P829, Q792Q4, Q7SXM7, Q7ZTZ2, Q8BFR6, Q8CCF0, Q8ISQ3, Q8K339, Q8TCF1

Diamond homologs: Q21755, Q3SWY5, Q4R7H4, Q5U3S7, Q6NUH3, Q6P829, Q9D6T0, Q9VWV8, Q9Y314, Q9SY88, Q55DU4, Q2U5W8, Q4WVU5

SIGNOR signaling

2 interactions.

AEffectBMechanism
NOSIP“down-regulates quantity by destabilization”PPP2CAubiquitination
NOSIP“up-regulates activity”EPORubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

53 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance39
Likely benign0
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2754 predictions. Top by Δscore:

VariantEffectΔscore
19:49556311:TCTTA:Tdonor_loss1.0000
19:49556312:CTTAC:Cdonor_loss1.0000
19:49556313:TTACC:Tdonor_loss1.0000
19:49556314:TAC:Tdonor_loss1.0000
19:49556315:A:ACdonor_gain1.0000
19:49556315:AC:Adonor_gain1.0000
19:49556315:ACC:Adonor_gain1.0000
19:49556315:ACCCG:Adonor_gain1.0000
19:49556316:C:CCdonor_gain1.0000
19:49556316:CC:Cdonor_gain1.0000
19:49556316:CCC:Cdonor_gain1.0000
19:49556316:CCCG:Cdonor_gain1.0000
19:49556316:CCCGC:Cdonor_gain1.0000
19:49556421:CCCCA:Cacceptor_gain1.0000
19:49556422:CCCA:Cacceptor_gain1.0000
19:49556422:CCCAC:Cacceptor_gain1.0000
19:49556423:CCA:Cacceptor_gain1.0000
19:49556423:CCAC:Cacceptor_gain1.0000
19:49556424:CA:Cacceptor_gain1.0000
19:49556424:CAC:Cacceptor_gain1.0000
19:49556426:C:CCacceptor_gain1.0000
19:49556438:C:Tacceptor_gain1.0000
19:49556547:A:ACdonor_gain1.0000
19:49556548:C:CTdonor_gain1.0000
19:49556548:CG:Cdonor_gain1.0000
19:49556732:CGGGA:Cacceptor_gain1.0000
19:49556733:GGGA:Gacceptor_gain1.0000
19:49556734:GGA:Gacceptor_gain1.0000
19:49556735:GA:Gacceptor_gain1.0000
19:49556735:GACTG:Gacceptor_loss1.0000

AlphaMissense

1937 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
19:49560024:C:TG29E1.000
19:49560638:C:AE18D1.000
19:49560638:C:GE18D1.000
19:49560652:A:GY14H1.000
19:49560682:G:CH4D1.000
19:49555808:G:CF283L0.999
19:49555808:G:TF283L0.999
19:49555810:A:GF283L0.999
19:49556414:A:TV246D0.999
19:49556607:A:GC223R0.999
19:49556923:C:AW163C0.999
19:49556923:C:GW163C0.999
19:49556925:A:GW163R0.999
19:49556925:A:TW163R0.999
19:49556926:G:CF162L0.999
19:49556926:G:TF162L0.999
19:49556928:A:GF162L0.999
19:49558970:C:TG62D0.999
19:49559972:A:CC46W0.999
19:49559974:A:GC46R0.999
19:49559995:C:GA39P0.999
19:49560025:C:AG29W0.999
19:49560025:C:GG29R0.999
19:49560025:C:TG29R0.999
19:49560626:G:CD22E0.999
19:49560626:G:TD22E0.999
19:49560628:C:GD22H0.999
19:49560639:T:AE18V0.999
19:49560640:C:TE18K0.999
19:49560648:G:AT15I0.999

dbSNP variants (sampled 300 via entrez): RS1000145770 (19:49572268 G>C), RS1000148676 (19:49562154 T>C), RS1000256329 (19:49566342 C>T), RS1000273297 (19:49567254 C>T), RS1000332089 (19:49580610 C>T), RS1000542503 (19:49554972 G>A), RS1000546902 (19:49561241 T>C), RS1000834611 (19:49574844 C>T), RS1000883726 (19:49578734 C>T), RS1001051476 (19:49555690 G>A,T), RS1001089700 (19:49566524 C>T), RS1001200175 (19:49571069 T>C,G), RS1001352604 (19:49555482 C>A,T), RS1001481452 (19:49576975 G>T), RS1001661280 (19:49565194 C>T)

Disease associations

OMIM: gene MIM:616759 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

StudyTraitp-value
GCST002539_91Schizophrenia5.000000e-08
GCST004601_194Red blood cell count8.000000e-12
GCST004604_44Hematocrit1.000000e-10
GCST008155_28Waist-hip ratio2.000000e-06
GCST008159_53Waist-to-hip ratio adjusted for BMI3.000000e-06
GCST90002383_293Hematocrit1.000000e-18
GCST90002384_467Hemoglobin4.000000e-21

EFO canonical traits (5, from GWAS)

EFO IDTrait name
EFO:0004305erythrocyte count
EFO:0004348hematocrit
EFO:0004343waist-hip ratio
EFO:0007788BMI-adjusted waist-hip ratio
EFO:0004509hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724614 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
sodium arsenitedecreases expression, increases expression2
Valproic Acidincreases methylation, increases expression2
aristolochic acid Iincreases expression1
TAK-243increases sumoylation1
bisphenol Adecreases expression1
trichostatin Aaffects expression1
beta-lapachoneincreases expression1
butyraldehydeincreases expression1
coumarindecreases phosphorylation1
di-n-butylphosphoric acidaffects expression1
CGP 52608affects binding, increases reaction1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
ICG 001decreases expression1
abrineincreases expression1
LDN 193189decreases expression, affects cotreatment1
(+)-JQ1 compounddecreases expression1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic aciddecreases expression1
Temozolomideincreases expression1
Vorinostatincreases expression1
Acetaminophenincreases expression1
Benzo(a)pyrenedecreases methylation1
Caffeineaffects phosphorylation1
Copperaffects binding, decreases expression1
Disulfiramaffects binding, decreases expression1
Doxorubicindecreases expression1
Enzyme Inhibitorsdecreases activity, increases O-linked glycosylation1
Ivermectindecreases expression1
Leadaffects expression1
Ribonucleotidesaffects binding1
Rotenoneincreases expression1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5697276BindingInhibition of NOSIP (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysisInhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_B3CLAbcam HEK293T NOSIP KOTransformed cell lineFemale

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.