SYVN1

Summary

SYVN1 (synoviolin 1, HGNC:20738) is a protein-coding gene on chromosome 11q13.1, encoding E3 ubiquitin-protein ligase synoviolin (Q86TM6). E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC7 E2 ligase and transfers it to substrates, promoting their degradation. It is a selective cancer dependency (DepMap: 33.8% of cell lines).

This gene encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The encoded protein removes unfolded proteins, accumulated during ER stress, by retrograde transport to the cytosol from the ER. This protein also uses the ubiquitin-proteasome system for additional degradation of unfolded proteins. Sequence analysis identified two transcript variants that encode different isoforms.

Source: NCBI Gene 84447 — RefSeq curated summary.

At a glance

• Gene–disease (curated): schizophrenia (No Known Disease Relationship, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 94 total
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 33.8% of screened cell lines
• MANE Select transcript: NM_172230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20738
Approved symbol	SYVN1
Name	synoviolin 1
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	HRD1, DER3
Ensembl gene	ENSG00000162298
Ensembl biotype	protein_coding
OMIM	608046
Entrez	84447

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 25 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000294256, ENST00000307289, ENST00000377190, ENST00000449943, ENST00000525874, ENST00000526060, ENST00000526121, ENST00000527142, ENST00000527765, ENST00000528487, ENST00000529207, ENST00000530451, ENST00000531018, ENST00000532771, ENST00000533685, ENST00000904688, ENST00000904689, ENST00000904690, ENST00000904691, ENST00000904692, ENST00000904693, ENST00000904694, ENST00000904695, ENST00000904696, ENST00000904697, ENST00000904698, ENST00000904699, ENST00000904700, ENST00000904701, ENST00000904702, ENST00000904703, ENST00000904704, ENST00000904705, ENST00000918753

RefSeq mRNA: 2 — MANE Select: NM_172230 NM_032431, NM_172230

CCDS: CCDS31605, CCDS8097

Canonical transcript exons

ENST00000377190 — 16 exons

Exon	Start	End
ENSE00001063987	65130251	65130379
ENSE00001120087	65132732	65132780
ENSE00001473063	65130002	65130175
ENSE00001805107	65128563	65128714
ENSE00002143802	65134456	65134519
ENSE00002168773	65127279	65128488
ENSE00003489942	65132248	65132351
ENSE00003496155	65132922	65133074
ENSE00003518088	65133160	65133252
ENSE00003545993	65129729	65129915
ENSE00003555579	65130920	65131036
ENSE00003578580	65133470	65133618
ENSE00003610865	65130660	65130823
ENSE00003622829	65131470	65131596
ENSE00003658227	65131132	65131197
ENSE00003791254	65131274	65131373

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 97.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.2842 / max 332.3216, expressed in 1813 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120538	16.1229	1801
120537	14.8639	1803
120539	1.6654	1181
120536	1.1893	787
120535	0.3648	53
120534	0.0779	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.97	gold quality
body of pancreas	UBERON:0001150	97.47	gold quality
right lobe of liver	UBERON:0001114	97.03	gold quality
bone marrow cell	CL:0002092	96.57	gold quality
pancreas	UBERON:0001264	96.08	gold quality
vermiform appendix	UBERON:0001154	95.95	gold quality
stromal cell of endometrium	CL:0002255	95.86	gold quality
islet of Langerhans	UBERON:0000006	95.57	gold quality
right lobe of thyroid gland	UBERON:0001119	95.18	gold quality
lymph node	UBERON:0000029	94.93	gold quality
left lobe of thyroid gland	UBERON:0001120	94.76	gold quality
spleen	UBERON:0002106	94.68	gold quality
body of stomach	UBERON:0001161	94.55	gold quality
adenohypophysis	UBERON:0002196	94.54	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.24	gold quality
minor salivary gland	UBERON:0001830	94.23	gold quality
tonsil	UBERON:0002372	94.05	gold quality
left uterine tube	UBERON:0001303	94.01	gold quality
left adrenal gland cortex	UBERON:0035825	93.94	gold quality
left adrenal gland	UBERON:0001234	93.93	gold quality
right adrenal gland	UBERON:0001233	93.79	gold quality
thyroid gland	UBERON:0002046	93.76	gold quality
rectum	UBERON:0001052	93.69	gold quality
saliva-secreting gland	UBERON:0001044	93.66	gold quality
pituitary gland	UBERON:0000007	93.59	gold quality
right ovary	UBERON:0002118	93.56	gold quality
granulocyte	CL:0000094	93.50	gold quality
right adrenal gland cortex	UBERON:0035827	93.39	gold quality
endocervix	UBERON:0000458	93.21	gold quality
stomach	UBERON:0000945	93.21	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	37.93
E-ANND-3	yes	31.28
E-MTAB-9067	yes	19.11
E-MTAB-9801	yes	3.92
E-MTAB-6379	no	41.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, GABPA, TP53, XBP1

miRNA regulators (miRDB)

83 targeting SYVN1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-7150	99.62	66.80	1322

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 33.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• HRD1 protects against endoplasmic reticulum stress-induced apoptosis through endoplasmic reticulum-associated degradation. (PMID:12459480)
• endogenous hHrd1 resides in the ER and has a ubiquitin-ligase activity (PMID:12646171)
• Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum (PMID:14593114)
• Results showed that Synoviolin, a novel causative factor for rheumatoid arthritis, is up-regulated in proliferating synovial cells in the disease. (PMID:16786162)
• Elevated peripheral blood (PB) levels of synoviolin were associated with nonresponse to infliximab treatment. Upregulation of synoviolin by IL-lbeta and TNFalpha may contribute to prolonged survival of immune cells and rheumatoid arthritis chronicity. (PMID:16802346)
• These results suggest that Hrd1 is a novel htt-interacting protein that can target pathogenic httN for degradation and is able to protect cells against httN-induced cell death. (PMID:17141218)
• the endoplasmic reticulum-resident ubiquitin ligase ‘Synoviolin’ destroys p53 (PMID:17170702)
• Review. In addition to its canonical role in endoplasmic-reticulum-associated degradation, synoviolin targets tumor suppressor gene p53 for proteasomal degradation, suggesting crosstalk between ERAD and p53 mediated apoptotic pathway under ER stress. (PMID:17582219)
• endoplasmic reticulum stress-induced HRD1 and SEL1 expressions are mediated by IRE1-XBP1- and ATF6-dependent pathways, respectively (PMID:17967421)
• overexpressed in the synovial cells of patients with rheumatoid arthritis, resulting in a state in which the cell deals with accumulated unfolded proteins excessively (PMID:18235538)
• OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD (PMID:18264092)
• These findings reveal a role for SEL1L and HRD1 in IgM quality control. (PMID:18314878)
• proline-rich domain of HRD1 is necessary to promote the degradation of Pael-R and that the protein’s transmembrane domain is necessary to transfer Pael-R from the endoplasmic reticulum (ER) to the cytosol. (PMID:18344614)
• XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP (PMID:18502753)
• analysed the promoter of human HRD1, which encodes an E3 ubiquitin ligase, an important component of ERAD (PMID:18664523)
• ILF-3, which has been known to regulate IL-2 expression in T cells, up-regulates synoviolin expression with GABPalpha in rheumatoid synovial cells (PMID:19116932)
• involved in endoplasmic reticulum-associated degradation that protects against ER stress-induced cell death.(review) (PMID:19443960)
• The results support that gp78 is an E3 targeting CFTRDeltaF508 for degradation and Hrd1 inhibits CFTRDeltaF508 degradation by acting as an E3 for gp78. (PMID:19828134)
• Hrd1 targets gp78 for proteasomal degradation independent of the ubiquitin ligase activity of gp78, without evidence of a reciprocal effect. (PMID:19835843)
• These data demonstrate a role of the E3 ubiquitin ligases in CTA1 retro-translocation. (PMID:19864457)
• HRD1 promotes ubiquitination and degradation of amyloid precursor protein (APP) that leads to decreased amyloid beta production, whereas HRD1 loss in Alzheimer’s disease leads to accumulation of APP and increased levels of amyloid beta. (PMID:20237263)
• serine-dependent, HRD1-mediated ubiquitination targets TCRalpha to the ERAD pathway (PMID:20519503)
• Using brain tissue from Alzheimer’s disease and normal subjects, a negative correlation was found between the expressed levels of HRD1 and of amyloid-beta; this suggests the possible involvement of HRD1 in amyloid-beta generation. (PMID:20606367)
• binding of Herp to Hrd1-containing ERAD complexes positively regulates the ubiquitylation activity of these complexes, thus permitting survival of the cell during ER stress. (PMID:21149444)
• data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression (PMID:21245296)
• regulation of the stability and assembly of the HRD1-SEL1L complex is critical to optimize the degradation kinetics of ERAD substrates (PMID:21454652)
• Hrd1 functions as an E3 targeting tau or abnormal p-tau for proteasome degradation. (PMID:22280354)
• Synoviolin up-regulates amyloid beta production by targeting a negative regulator of gamma-secretase, Rer1, for degradation. (PMID:23129766)
• ERdj5, by binding to Sel1L, triggers BiP-Cholera toxin interaction proximal to the Hrd1 complex; postulate this scenario enables the Hrd1-associated retrotranslocation machinery to capture the toxin efficiently once the toxin is released from BiP (PMID:23363602)
• derlin2 functions with HRD1 in ERAD of certain substrates independent of their glycosylation status. (PMID:23867461)
• subset of integral membrane proteins, therefore, requires an early dislocation event to expose part of their luminal domain to the cytosol, before HRD1-mediated polyubiquitination and dislocation (PMID:23929775)
• the interactions between P97 and these motifs, including VCP-binding motif (VBM) and VCP-interacting motif (VIM). The solution structures of the VBM motif from HRD1 and the VIM motif from SVIP are both comprised mainly of a single alpha-helix. (PMID:24100225)
• a new HRD1-associated membrane protein named HERP2, which is homologous to the previously identified HRD1 partner HERP1. Despite sequence homology, HERP2 is constitutively expressed in cells, whereas HERP1 is highly induced by ER stress. (PMID:24366871)
• Herp localizes to the endoplasmic reticulum-derived quality control compartment (ERQC) and recruits HRD1, which targets to endoplasmic reticulum associated degradation the substrate presented by the OS-9 lectin at the ERQC. (PMID:24478453)
• Results show that HRD1 and RFP2 contributes are required for the disposal of V247M alpha-sarcoglycan mutant. (PMID:24565866)
• HRD1 and RMA1 may therefore be negative regulators of disease-associated transporter ABCG5/ABCG8. (PMID:24584735)
• identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis (PMID:24636985)
• Charcot-Marie-Tooth disease-related PMP22 is trapped in the endoplasmic reticulum by calnexin-dependent retention and Rer1-mediated early Golgi retrieval systems and partly degraded by the Hrd1-mediated endoplasmic reticulum-associated degradation system. (PMID:25385046)
• specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. (PMID:26107514)
• The inherently unstable nature of the human SEL1L protein lies in its transmembrane domain, and that association of HRD1 with the SEL1L transmembrane domain restored its stability. (PMID:26471130)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	syvn1	ENSDARG00000017842
mus_musculus	Syvn1	ENSMUSG00000024807
rattus_norvegicus	Syvn1	ENSRNOG00000020950
drosophila_melanogaster	sip3	FBGN0039875
caenorhabditis_elegans		WBGENE00004768

Paralogs (4): RNF145 (ENSG00000145860), AMFR (ENSG00000159461), RNF139 (ENSG00000170881), DZIP3 (ENSG00000198919)

Protein

Protein identifiers

E3 ubiquitin-protein ligase synoviolin — Q86TM6 (reviewed: Q86TM6)

Alternative names: RING-type E3 ubiquitin transferase synoviolin, Synovial apoptosis inhibitor 1

All UniProt accessions (5): E9PK19, E9PMA1, E9PN88, Q86TM6, H0YCR6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC7 E2 ligase and transfers it to substrates, promoting their degradation. Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Also promotes the degradation of normal but naturally short-lived proteins such as SGK. Protects cells from ER stress-induced apoptosis. Protects neurons from apoptosis induced by polyglutamine-expanded huntingtin (HTT) or unfolded GPR37 by promoting their degradation. Sequesters p53/TP53 in the cytoplasm and promotes its degradation, thereby negatively regulating its biological function in transcription, cell cycle regulation and apoptosis. Mediates the ubiquitination and subsequent degradation of cytoplasmic NFE2L1. During the early stage of B cell development, required for degradation of the pre-B cell receptor (pre-BCR) complex, hence supporting further differentiation into mature B cells.

Subunit / interactions. Homodimer. Interacts with p53/TP53. Interacts with HTT. Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1. FAM8A1 is stabilized by interaction with SYNV1, which prevents its proteasomal degradation. OS9 and UBE2J1 recruitment to the complex may be mediated by SEL1L. SYNV1 assembles with SEL1L and FAM8A1 through its transmembrane domains, but interaction with its cytoplasmic domain is required to confer stability to FAM8A1 and enhance recruitment of HERPUD1. The HRD1 complex also associates with VIMP and may transfer misfolded proteins from the endoplasmic reticulum to VCP. May form a complex with ERLEC1, HSPA5, OS9 and SEL1L. Interacts with VCP. Interacts with UBXN6. Interacts with BAG6. Interacts with NFE2L1. Interacts (via N-terminus) with components of the pre-B cell receptor, including IGLL1 and VPREB1. Interacts with CREB3L3; this interaction leads to CREB3L3 ubiquitination and proteasomal degradation.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitously expressed, with highest levels in liver and kidney (at protein level). Up-regulated in synovial tissues from patients with rheumatoid arthritis (at protein level).

Post-translational modifications. Not N-glycosylated. Auto-ubiquitinated. Deubiquitinated by USP19.

Disease relevance. In certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), plays a role in the degradation of misfolded N-terminal mutated PRDM1 proteins.

Domain organisation. The RING-type zinc finger is required for E3 ligase activity.

Induction. By endoplasmic reticulum stress-inducing agents such as thapsigargin, tunicamycin or brefeldin A, but not by heat shock.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the HRD1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86TM6-1	1, b, long	yes
Q86TM6-2	2
Q86TM6-3	3, a, short

RefSeq proteins (2): NP_115807, NP_757385* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR050731	HRD1_E3_ubiq-ligases	Family
IPR057992	TPR_SYVN1_N	Domain
IPR058051	Znf_RING_synoviolin	Domain

Pfam: PF13639, PF25563

UniProt features (65 total): helix 11, binding site 8, topological domain 7, region of interest 7, transmembrane region 6, strand 6, compositionally biased region 4, mutagenesis site 4, turn 4, splice variant 2, sequence conflict 2, chain 1, zinc finger region 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8KET	ELECTRON MICROSCOPY	3.3
8KES	ELECTRON MICROSCOPY	3.5
8KEV	ELECTRON MICROSCOPY	3.5
9LWU	ELECTRON MICROSCOPY	3.5
9OG0	ELECTRON MICROSCOPY	3.64
9UAV	ELECTRON MICROSCOPY	3.7
6A3Z	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TM6-F1	73.97	0.36

Functional residue map

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

Ligand- & substrate-binding residues (8): 291; 294; 307; 309; 312; 315; 326; 329

Post-translational modifications (1): 613

Mutagenesis-validated functional residues (4):

Position	Phenotype
294	no effect on interaction with fam8a1, herpud1, os9, sel1l and ube2j1.
315	decreased ’lys-48’-linked ubiquitination.
329	abolishes e3 ligase activity.
503	loss of interaction with fam8a1, herpud1, os9 and ube2j1, impaired degradation of immature core-glycosylated basigin/cd1

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-901032	ER Quality Control Compartment (ERQC)
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-2262752	Cellular responses to stress
R-HSA-381070	IRE1alpha activates chaperones
R-HSA-381119	Unfolded Protein Response (UPR)
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5387390	Hh mutants abrogate ligand secretion
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-597592	Post-translational protein modification
R-HSA-8953897	Cellular responses to stimuli
R-HSA-901042	Calnexin/calreticulin cycle

MSigDB gene sets: 192 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_B_CELL_ACTIVATION, LFA1_Q6, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AP4_Q6, GGGTGGRR_PAX4_03, chr11q13, CAGCTG_AP4_Q5

GO Biological Process (11): immature B cell differentiation (GO:0002327), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), retrograde protein transport, ER to cytosol (GO:0030970), ERAD pathway (GO:0036503), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein stabilization (GO:0050821), protein K48-linked ubiquitination (GO:0070936), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), endoplasmic reticulum mannose trimming (GO:1904380), negative regulation of T-helper 1 type immune response (GO:0002826)

GO Molecular Function (10): zinc ion binding (GO:0008270), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), ATPase binding (GO:0051117), ubiquitin protein ligase activity (GO:0061630), DNA-binding transcription factor binding (GO:0140297), ubiquitin-specific protease binding (GO:1990381), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): Hrd1p ubiquitin ligase complex (GO:0000836), Hrd1p ubiquitin ligase ERAD-L complex (GO:0000839), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), smooth endoplasmic reticulum (GO:0005790), endomembrane system (GO:0012505), membrane (GO:0016020), Derlin-1 retrotranslocation complex (GO:0036513), endoplasmic reticulum quality control compartment (GO:0044322)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
IRE1alpha activates chaperones	1
Signaling by Hedgehog	1
Hh mutants abrogate ligand secretion	1
Calnexin/calreticulin cycle	1
Cellular responses to stimuli	1
Unfolded Protein Response (UPR)	1
Cellular responses to stress	1
Post-translational protein modification	1
Asparagine N-linked glycosylation	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1
Metabolism of proteins	1
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
proteasomal protein catabolic process	2
endoplasmic reticulum	2
B cell differentiation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
response to endoplasmic reticulum stress	1
response to chemical	1
ubiquitin-dependent protein catabolic process	1
regulation of protein stability	1
protein polyubiquitination	1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
negative regulation of response to endoplasmic reticulum stress	1
negative regulation of intrinsic apoptotic signaling pathway	1
protein alpha-1,2-demannosylation	1
endoplasmic reticulum quality control compartment	1
negative regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
transition metal ion binding	1
protein binding	1
enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
transcription factor binding	1
protease binding	1
binding	1
catalytic activity	1
cation binding	1
ER ubiquitin ligase complex	1
Hrd1p ubiquitin ligase complex	1
nuclear lumen	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1476 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYVN1	SEL1L	Q9UBV2	999
SYVN1	DERL1	Q9BUN8	986
SYVN1	DERL2	Q9GZP9	956
SYVN1	OS9	Q13438	956
SYVN1	VCP	P55072	940
SYVN1	FAF2	Q96CS3	929
SYVN1	MARCHF6	O60337	908
SYVN1	UBE2J1	Q9Y385	905
SYVN1	HSPA5	P11021	890
SYVN1	AUP1	Q9Y679	882
SYVN1	CANX	P27824	876
SYVN1	EDEM1	Q92611	845
SYVN1	UFD1	Q92890	843
SYVN1	P4HB	P07237	822
SYVN1	SEC61A1	P38378	810

IntAct

161 interactions, top by confidence:

A	B	Type	Score
UBXN6	VCP	psi-mi:“MI:0915”(physical association)	0.960
SEL1L	OS9	psi-mi:“MI:0914”(association)	0.860
VCP	ATXN3	psi-mi:“MI:0914”(association)	0.830
FAM8A1	SYVN1	psi-mi:“MI:0915”(physical association)	0.790
SYVN1	FAM8A1	psi-mi:“MI:0914”(association)	0.790
FAM8A1	SYVN1	psi-mi:“MI:0914”(association)	0.790
FAM8A1	SYVN1	psi-mi:“MI:0403”(colocalization)	0.790
SYVN1	SEL1L	psi-mi:“MI:0914”(association)	0.770
SEL1L	SYVN1	psi-mi:“MI:0914”(association)	0.770
SYVN1	SEL1L	psi-mi:“MI:0915”(physical association)	0.770
AUP1	UBE2G2	psi-mi:“MI:0914”(association)	0.750
UBE2J1	SYVN1	psi-mi:“MI:0915”(physical association)	0.700
SYVN1	OS9	psi-mi:“MI:0914”(association)	0.690
OS9	SYVN1	psi-mi:“MI:0914”(association)	0.690
SYVN1	USP15	psi-mi:“MI:0915”(physical association)	0.670
SYVN1	USP15	psi-mi:“MI:0407”(direct interaction)	0.670

BioGRID (568): RER1 (Affinity Capture-Western), SYVN1 (Co-fractionation), SYVN1 (Affinity Capture-MS), SYVN1 (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), SYVN1 (Biochemical Activity), UBE2D2 (Reconstituted Complex), Ube2g2 (Reconstituted Complex), SYVN1 (Affinity Capture-MS), SYVN1 (Affinity Capture-MS), PSMB4 (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMOX1 (Affinity Capture-MS), PSMA7 (Affinity Capture-MS)

ESM2 similar proteins: A0M8T1, A3KN28, A4D7R9, A9JRA0, D3ZEH5, F1MK05, O60337, Q07DV5, Q07DW9, Q07E45, Q09YH4, Q09YI5, Q09YJ7, Q09YK8, Q0VCK9, Q108U3, Q28DS3, Q2HJD0, Q2IBE0, Q2IBE8, Q2QL86, Q2QLA6, Q2QLB7, Q2QLD7, Q2QLE8, Q2TBU2, Q3SZ48, Q3TDN2, Q4R910, Q4V888, Q5PPX5, Q5R9W1, Q68FW3, Q6GM44, Q6NYF1, Q6P4H8, Q6ZQ89, Q7SZN2, Q86TM6, Q8CBG9

Diamond homologs: A8WWR3, O22197, O22283, O60106, P30631, P90859, Q07G42, Q0II22, Q2KHN1, Q2TBT8, Q641J8, Q6AVN2, Q6DIP3, Q6IRP0, Q6NRL6, Q7T037, Q7TPV2, Q803I8, Q852U6, Q86TM6, Q86Y13, Q8RXD3, Q91YL2, Q940T5, Q94AK4, Q9BV68, Q9DBY1, Q9FLC6, Q9LQX2, Q9M2S6, Q9NVW2, Q9SNB6, Q9VE61, Q9VHI7, Q9VI20, Q9WTV7, A8Y4B2, F1MM41, F4I2Y3, F7EP40

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
FAM8A1	“up-regulates activity”	SYVN1	binding
SYVN1	“up-regulates activity”	HERPUD1	binding
SYVN1	“down-regulates quantity by destabilization”	NFE2L2	ubiquitination
Ub:E2	“up-regulates activity”	SYVN1	ubiquitination
SYVN1	“down-regulates quantity by destabilization”	GPR37	polyubiquitination
SYVN1	“down-regulates quantity by destabilization”	SERPINI1	polyubiquitination
SYVN1	“down-regulates quantity by destabilization”	APP	ubiquitination
SYVN1	“down-regulates quantity by destabilization”	EIF2S1	ubiquitination
SYVN1	“down-regulates quantity by destabilization”	GPR37	ubiquitination
SYVN1	“down-regulates quantity”	CPT2	ubiquitination
SYVN1	“down-regulates quantity by destabilization”	PTEN	ubiquitination
SYVN1	“down-regulates quantity by destabilization”	CDKN1B	ubiquitination
UBE2G2	“up-regulates activity”	SYVN1	ubiquitination
SYVN1	“down-regulates quantity by destabilization”	HMGCR	polyubiquitination
SYVN1	“down-regulates quantity by destabilization”	CLU	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Defective CFTR causes cystic fibrosis	7	15.1×	2e-04
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	7	13.3×	2e-04
Hh mutants are degraded by ERAD	5	11.9×	6e-03
Hedgehog ligand biogenesis	5	10.4×	9e-03
ABC-family protein mediated transport	8	9.5×	3e-04
Disorders of transmembrane transporters	6	8.2×	8e-03
SLC-mediated transmembrane transport	9	5.2×	6e-03
Transport of small molecules	17	4.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
retrograde protein transport, ER to cytosol	6	40.7×	2e-06
ERAD pathway	17	21.1×	4e-15
endoplasmic reticulum unfolded protein response	7	14.2×	2e-04
sodium ion transport	6	11.2×	3e-03
monoatomic ion transmembrane transport	7	10.0×	1e-03
sodium ion transmembrane transport	6	8.3×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3097 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65121817:GGCGA:G	acceptor_gain	1.0000
11:65121818:GCGA:G	acceptor_gain	1.0000
11:65121819:CGA:C	acceptor_gain	1.0000
11:65121819:CGAC:C	acceptor_gain	1.0000
11:65121820:GA:G	acceptor_gain	1.0000
11:65121822:C:CC	acceptor_gain	1.0000
11:65121822:C:T	acceptor_loss	1.0000
11:65121826:G:GC	acceptor_gain	1.0000
11:65122085:CTTA:C	donor_loss	1.0000
11:65122086:TTA:T	donor_loss	1.0000
11:65122087:TA:T	donor_loss	1.0000
11:65122088:ACCTG:A	donor_loss	1.0000
11:65122089:C:CA	donor_loss	1.0000
11:65125480:T:A	acceptor_gain	1.0000
11:65125482:TTGCA:T	acceptor_loss	1.0000
11:65125483:T:A	acceptor_gain	1.0000
11:65125483:TGCAG:T	acceptor_loss	1.0000
11:65125485:CAGA:C	acceptor_loss	1.0000
11:65125486:A:AG	acceptor_gain	1.0000
11:65125486:A:C	acceptor_loss	1.0000
11:65125487:G:GG	acceptor_gain	1.0000
11:65125487:GA:G	acceptor_gain	1.0000
11:65125487:GAC:G	acceptor_gain	1.0000
11:65125487:GACC:G	acceptor_gain	1.0000
11:65125487:GACCC:G	acceptor_gain	1.0000
11:65125592:A:T	donor_gain	1.0000
11:65125598:G:GT	donor_gain	1.0000
11:65125608:TCTGG:T	donor_gain	1.0000
11:65125610:TGG:T	donor_gain	1.0000
11:65125611:GG:G	donor_gain	1.0000

AlphaMissense

4008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65129774:G:T	A517D	1.000
11:65129775:C:G	A517P	1.000
11:65130767:A:T	V333D	1.000
11:65130777:G:A	R330C	1.000
11:65130777:G:T	R330S	1.000
11:65130778:G:C	C329W	1.000
11:65130779:C:A	C329F	1.000
11:65130779:C:G	C329S	1.000
11:65130779:C:T	C329Y	1.000
11:65130780:A:G	C329R	1.000
11:65130780:A:T	C329S	1.000
11:65130785:G:A	P327L	1.000
11:65130785:G:C	P327R	1.000
11:65130785:G:T	P327H	1.000
11:65130786:G:A	P327S	1.000
11:65130786:G:T	P327T	1.000
11:65130787:G:C	C326W	1.000
11:65130788:C:A	C326F	1.000
11:65130788:C:G	C326S	1.000
11:65130788:C:T	C326Y	1.000
11:65130789:A:C	C326G	1.000
11:65130789:A:G	C326R	1.000
11:65130789:A:T	C326S	1.000
11:65130800:C:G	R322P	1.000
11:65130805:G:C	F320L	1.000
11:65130805:G:T	F320L	1.000
11:65130806:A:C	F320C	1.000
11:65130806:A:G	F320S	1.000
11:65130807:A:G	F320L	1.000
11:65130808:C:A	W319C	1.000

dbSNP variants (sampled 300 via entrez): RS1000144991 (11:65134953 A>T), RS1000433292 (11:65135202 A>C,G), RS1000502807 (11:65134850 G>A), RS1001874421 (11:65134434 G>C,T), RS1001904475 (11:65135746 C>T), RS1001935466 (11:65135396 A>C), RS1002279689 (11:65134563 T>C,G), RS1003252388 (11:65130876 G>A,C), RS1003696273 (11:65130571 G>A), RS1003890450 (11:65127755 G>A,T), RS1004272883 (11:65131869 G>A), RS1004285490 (11:65134862 C>T), RS1004426021 (11:65134238 C>T), RS1005115406 (11:65128001 T>A), RS1005280053 (11:65133382 C>G,T)

Disease associations

OMIM: gene MIM:608046 | disease phenotypes: MIM:300633

GenCC curated gene-disease

Disease	Classification	Inheritance
schizophrenia	No Known Disease Relationship	Unknown

Mondo (4): hypospadias (MONDO:0005345), encephalomalacia (MONDO:0006741), periventricular leukomalacia (MONDO:0015742), schizophrenia (MONDO:0005090)

Orphanet (2): OBSOLETE: Familial hypospadias (Orphanet:440), NON RARE IN EUROPE: Periventricular leukomalacia (Orphanet:171676)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000047	Hypospadias

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010577_17	Crohn’s disease	2.000000e-06

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004678	Encephalomalacia	C10.228.140.461
D007021	Hypospadias	C12.050.351.875.466; C12.100.500.494.400; C12.200.294.494.400; C12.200.706.516; C12.800.516; C16.131.939.516
D007969	Leukomalacia, Periventricular	C10.228.140.300.700; C10.228.140.461.550; C14.907.253.612; C16.614.521.450

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067180 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.13	Kd	7.335	nM	CHEMBL5653589
8.13	ED50	7.335	nM	CHEMBL5653589
6.79	Kd	162.1	nM	CHEMBL3752910
6.79	ED50	162.1	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149536: Binding affinity to human SYVN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0073	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149536: Binding affinity to human SYVN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1621	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression, affects cotreatment, affects expression	5
Particulate Matter	increases abundance, increases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tunicamycin	increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Thapsigargin	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	increases expression	1
ochratoxin A	decreases expression	1
boric acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-phenylbutyric acid	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol S	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Cholic Acids	affects cotreatment, affects expression	1
Curcumin	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652578	Binding	Binding affinity to human SYVN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8BV	Ubigene A-549 SYVN1 KO	Cancer cell line	Male
CVCL_D9TR	Ubigene HEK293 SYVN1 KO	Transformed cell line	Female
CVCL_F1LQ	HyCyte A-375 KO-hSYVN1	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety