RNF121

Summary

RNF121 (ring finger protein 121, HGNC:21070) is a protein-coding gene on chromosome 11q13.4, encoding E3 ubiquitin ligase RNF121 (Q9H920). E3 ubiquitin ligase which accepts ubiquitin and transfers it to substrates thereby promoting their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway which is a pathway involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum pro….

The protein encoded by this gene contains a RING finger, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. Several alternatively spliced transcript variants have been noted for this gene, however, not all are likely to encode viable protein products.

Source: NCBI Gene 55298 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_018320

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21070
Approved symbol	RNF121
Name	ring finger protein 121
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11099
Ensembl gene	ENSG00000137522
Ensembl biotype	protein_coding
OMIM	620529
Entrez	55298

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 13 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000361756, ENST00000393711, ENST00000393713, ENST00000490867, ENST00000525176, ENST00000525243, ENST00000526549, ENST00000526903, ENST00000528683, ENST00000530058, ENST00000530137, ENST00000530655, ENST00000532379, ENST00000533380, ENST00000900824, ENST00000900825, ENST00000900826, ENST00000900827, ENST00000900828, ENST00000940312, ENST00000940313, ENST00000940314, ENST00000945999

RefSeq mRNA: 2 — MANE Select: NM_018320 NM_001300926, NM_018320

CCDS: CCDS73343, CCDS8203

Canonical transcript exons

ENST00000361756 — 9 exons

Exon	Start	End
ENSE00001764192	71929046	71929124
ENSE00003497045	71994719	71994852
ENSE00003533862	71995450	71995551
ENSE00003553070	71996195	71997597
ENSE00003625793	71960750	71960891
ENSE00003651700	71982761	71982915
ENSE00003681693	71957227	71957264
ENSE00003685586	71990597	71990717
ENSE00003692154	71987004	71987111

Expression profiles

Bgee: expression breadth ubiquitous, 136 present calls, max score 95.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0202 / max 107.9260, expressed in 1786 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115698	12.9412	1786
115699	0.0790	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
quadriceps femoris	UBERON:0001377	95.86	silver quality
cerebellar vermis	UBERON:0004720	93.88	gold quality
thymus	UBERON:0002370	92.73	silver quality
stromal cell of endometrium	CL:0002255	92.20	gold quality
islet of Langerhans	UBERON:0000006	91.79	gold quality
duodenum	UBERON:0002114	89.79	gold quality
placenta	UBERON:0001987	88.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.00	gold quality
metanephros cortex	UBERON:0010533	87.91	gold quality
cortex of kidney	UBERON:0001225	87.78	gold quality
kidney	UBERON:0002113	87.73	gold quality
adult mammalian kidney	UBERON:0000082	87.71	gold quality
tonsil	UBERON:0002372	87.63	gold quality
popliteal artery	UBERON:0002250	87.59	gold quality
tibial artery	UBERON:0007610	87.59	gold quality
descending thoracic aorta	UBERON:0002345	87.49	gold quality
thoracic aorta	UBERON:0001515	87.30	gold quality
muscle of leg	UBERON:0001383	87.29	gold quality
ascending aorta	UBERON:0001496	87.29	gold quality
pancreas	UBERON:0001264	87.20	gold quality
mucosa of transverse colon	UBERON:0004991	87.20	gold quality
saliva-secreting gland	UBERON:0001044	87.04	gold quality
right coronary artery	UBERON:0001625	87.04	gold quality
prefrontal cortex	UBERON:0000451	87.00	gold quality
gastrocnemius	UBERON:0001388	86.90	gold quality
corpus callosum	UBERON:0002336	86.87	gold quality
left adrenal gland cortex	UBERON:0035825	86.87	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.85	gold quality
minor salivary gland	UBERON:0001830	86.80	gold quality
skeletal muscle tissue	UBERON:0001134	86.65	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting RNF121, 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-8485	100.00	77.57	4731
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-3938	98.72	66.07	834

Literature-anchored findings (GeneRIF, showing 5)

• This is the first study to demonstrate that RNF121 is a novel regulator of apoptosis and provides a new potential target for cancer therapy (PMID:24928685)
• These results unveil an unexpected role of Golgi Apparatus and reveal RNF121 as a new player involved in the signaling leading to NF-kappaB activation. (PMID:25388546)
• Over-expression of RNF121 promoted ubiquitination of VEGFR-2, inhibited its maturation . RNF121 knockdown in primary endothelial cells reduced VEGFR-2 ubiquitination and increased its cell surface level. (PMID:26602861)
• we identified and characterised oncogenic fusion genes and their function in CRC, and implicated NAGLU-IKZF3 and RNF121-FOLR2 as novel molecular targets for personalised medicine development. (PMID:29955133)
• Study found that RNF121 was less expressed in tumor tissues than adjacent normal tissues of renal cell carcinoma (RCC) patients. Overexpression of RNF121 inhibited the growth of human RCC cells in vivo. Moreover, RNF121 impeded the proliferation, migration and invasion of human RCC cells in vitro. In addition, RNF121 was found to activate NF-kappaB signaling pathway via promoting IkappaBalpha degradation in RCC cells. (PMID:30149063)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf121	ENSDARG00000060282
mus_musculus	Rnf121	ENSMUSG00000070426
rattus_norvegicus	Rnf121	ENSRNOG00000020175
drosophila_melanogaster	CG15814	FBGN0030873
caenorhabditis_elegans		WBGENE00007626

Paralogs (1): RNF175 (ENSG00000145428)

Protein

Protein identifiers

E3 ubiquitin ligase RNF121 — Q9H920 (reviewed: Q9H920)

Alternative names: RING finger protein 121

All UniProt accessions (9): C9JQY5, E9PKE9, E9PLR7, E9PN80, E9PRV6, Q9H920, F8WDV7, G3V148, H0YEH6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase which accepts ubiquitin and transfers it to substrates thereby promoting their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway which is a pathway involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. May regulate the unfolded protein response to reduce endoplasmic reticulum stress.

Subcellular location. Endoplasmic reticulum membrane.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RNF121 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H920-1	1	yes
Q9H920-2	2

RefSeq proteins (2): NP_001287855, NP_060790* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR040176	RNF121/RNF175	Family

UniProt features (12 total): transmembrane region 6, initiator methionine 1, chain 1, splice variant 1, sequence conflict 1, zinc finger region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H920-F1	84.94	0.52

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 (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): E2F_Q4_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GCANCTGNY_MYOD_Q6, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, chr11q13, CAGCTG_AP4_Q5, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_ERAD_PATHWAY, GOBP_PROTEIN_CATABOLIC_PROCESS, MARSON_BOUND_BY_FOXP3_STIMULATED, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOBP_PROTEOLYSIS

GO Biological Process (2): protein ubiquitination (GO:0016567), ERAD pathway (GO:0036503)

GO Molecular Function (4): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
catalytic activity	1
cation binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF121	SMIM9	A6NGZ8	482
RNF121	RNF130	Q86XS8	451
RNF121	KDR	P35968	447
RNF121	RNF5	Q99942	444
RNF121	RNFT1	Q5M7Z0	433
RNF121	RNF170	Q96K19	429
RNF121	MARCHF6	O60337	424
RNF121	UBE2G1	P62253	405
RNF121	RNF185	Q96GF1	401
RNF121	CGRRF1	Q99675	399
RNF121	PHYKPL	Q8IUZ5	396
RNF121	WDR37	Q9Y2I8	395
RNF121	ALKBH6	Q3KRA9	393
RNF121	NSRP1	Q9H0G5	379
RNF121	RNF145	Q96MT1	376

IntAct

13 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
rep	B4GALT3	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
CACNG6	TSPAN3	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC6A12	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC6A13	SPTLC2	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): NFKBIA (Affinity Capture-Western), RNF121 (Affinity Capture-MS), RNF121 (Affinity Capture-RNA), RNF121 (Biochemical Activity), RNF121 (Synthetic Lethality), RNF121 (Affinity Capture-MS), RNF121 (Affinity Capture-RNA), RNF121 (Affinity Capture-MS), RNF121 (Affinity Capture-MS), RNF121 (Affinity Capture-MS), RNF121 (Affinity Capture-MS), RNF121 (Affinity Capture-MS), RNF121 (Proximity Label-MS), RNF121 (Affinity Capture-Western), RNF121 (Proximity Label-MS)

ESM2 similar proteins: A0A8I3PI99, A0M8U1, A7Y521, B5DEN9, C5HGF3, O88544, O94973, P13666, P17427, P18484, P38024, Q00765, Q0VCK5, Q0X0A5, Q13098, Q1RLU8, Q28635, Q2PG42, Q3KNM2, Q3SZA0, Q3T0N3, Q3T126, Q3T178, Q3ZC24, Q4R5E6, Q5F418, Q5I0H4, Q5M7T4, Q5R648, Q5R9B0, Q5R9M4, Q5RE33, Q5ZJ41, Q5ZJD7, Q6DGW9, Q6GM44, Q6NRT5, Q7TQ48, Q8C407, Q8R1Z9

Diamond homologs: O94400, Q09251, Q6DD32, Q6P360, Q8N4F7, Q8R1Z9, Q9H920, A8WWR3, A8Y4B2, F1MM41, F7EP40, O22197, O22255, O22283, P0CH30, P30631, P90859, Q06003, Q0IJ20, Q14B02, Q20798, Q28GL3, Q2KHN1, Q3U2C5, Q566M8, Q5DTZ6, Q5M7Z0, Q5M974, Q5RBT7, Q5RF74, Q5SWK7, Q5XHH7, Q5Z880, Q66KG7, Q6AVN2, Q6AY01, Q6GPV5, Q6NPT7, Q6NRL6, Q6NRX0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF121	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2062 predictions. Top by Δscore:

Variant	Effect	Δscore
11:71960741:G:A	acceptor_gain	1.0000
11:71960746:TCA:T	acceptor_loss	1.0000
11:71960747:CA:C	acceptor_loss	1.0000
11:71960748:A:AG	acceptor_gain	1.0000
11:71960748:AG:A	acceptor_gain	1.0000
11:71960748:AGG:A	acceptor_gain	1.0000
11:71960748:AGGGT:A	acceptor_loss	1.0000
11:71960749:G:GT	acceptor_gain	1.0000
11:71960749:GG:G	acceptor_gain	1.0000
11:71960749:GGG:G	acceptor_gain	1.0000
11:71960749:GGGT:G	acceptor_gain	1.0000
11:71960749:GGGTC:G	acceptor_gain	1.0000
11:71960887:ACAAT:A	donor_gain	1.0000
11:71960888:CAAT:C	donor_gain	1.0000
11:71960888:CAATG:C	donor_loss	1.0000
11:71960889:AAT:A	donor_gain	1.0000
11:71960889:AATGT:A	donor_loss	1.0000
11:71960890:AT:A	donor_gain	1.0000
11:71960890:ATG:A	donor_loss	1.0000
11:71960891:TG:T	donor_loss	1.0000
11:71960892:G:GC	donor_loss	1.0000
11:71960892:G:GG	donor_gain	1.0000
11:71960893:TAAG:T	donor_loss	1.0000
11:71987001:CAG:C	acceptor_loss	1.0000
11:71987002:AGG:A	acceptor_loss	1.0000
11:71987002:AGGTT:A	acceptor_gain	1.0000
11:71987003:GGTTG:G	acceptor_gain	1.0000
11:71987107:TTCAA:T	donor_gain	1.0000
11:71987110:AAG:A	donor_loss	1.0000
11:71987111:AGTG:A	donor_loss	1.0000

AlphaMissense

2160 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:71960862:T:A	W72R	1.000
11:71960862:T:C	W72R	1.000
11:71982782:T:A	W89R	1.000
11:71982782:T:C	W89R	1.000
11:71987062:G:C	G153R	1.000
11:71994767:T:C	C226R	1.000
11:71994843:G:A	C251Y	1.000
11:71995463:T:C	C259R	1.000
11:71995464:G:A	C259Y	1.000
11:71995465:C:G	C259W	1.000
11:71995472:G:C	G262R	1.000
11:71995473:G:A	G262D	1.000
11:71995475:T:A	W263R	1.000
11:71995475:T:C	W263R	1.000
11:71995477:G:C	W263C	1.000
11:71995477:G:T	W263C	1.000
11:71995488:G:A	G267E	1.000
11:71995502:T:C	C272R	1.000
11:71996256:T:A	W309R	1.000
11:71996256:T:C	W309R	1.000
11:71960799:C:A	H51N	0.999
11:71960801:T:A	H51Q	0.999
11:71960801:T:G	H51Q	0.999
11:71960809:T:A	M54K	0.999
11:71960809:T:C	M54T	0.999
11:71960809:T:G	M54R	0.999
11:71960821:T:C	L58P	0.999
11:71982792:C:A	P92H	0.999
11:71982792:C:G	P92R	0.999
11:71982839:T:A	W108R	0.999

dbSNP variants (sampled 300 via entrez): RS1000023116 (11:71972914 C>T), RS1000083082 (11:71931861 T>C), RS1000098381 (11:71979779 A>C), RS1000110727 (11:71975499 AG>A,AGG), RS1000152911 (11:71937099 A>G), RS1000172673 (11:71936541 C>T), RS1000173809 (11:71979393 C>T), RS1000178130 (11:71965635 G>A), RS1000196570 (11:71993974 G>A), RS1000228524 (11:71949861 G>C), RS1000306337 (11:71956450 G>A), RS1000439609 (11:71973162 G>A,C), RS1000452534 (11:71949178 C>A,G,T), RS1000457057 (11:71992175 G>A), RS1000498789 (11:71977612 G>T)

Disease associations

OMIM: gene MIM:620529 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, decreases expression	2
chloroacetaldehyde	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
deguelin	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Cidofovir	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzene	increases expression	1
Ifosfamide	decreases expression	1
Oxygen	decreases expression	1
Rotenone	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Particulate Matter	increases abundance, decreases expression	1

Clinical trials (associated diseases)

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