RHBDL2

Summary

RHBDL2 (rhomboid like 2, HGNC:16083) is a protein-coding gene on chromosome 1p34.3, encoding Rhomboid-related protein 2 (Q9NX52). Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.

The protein encoded by this gene is a member of the rhomboid family of integral membrane proteins. This family contains proteins that are related to Drosophila rhomboid protein. Members of this family are found in both prokaryotes and eukaryotes and are thought to function as intramembrane serine proteases. The encoded protein is thought to release soluble growth factors by proteolytic cleavage of certain membrane-bound substrates, including ephrin B2 and ephrin B3. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54933 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_017821

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16083
Approved symbol	RHBDL2
Name	rhomboid like 2
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20435
Ensembl gene	ENSG00000158315
Ensembl biotype	protein_coding
OMIM	608962
Entrez	54933

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000289248, ENST00000372990, ENST00000540558, ENST00000863984

RefSeq mRNA: 2 — MANE Select: NM_017821 NM_001304746, NM_017821

CCDS: CCDS30680

Canonical transcript exons

ENST00000372990 — 8 exons

Exon	Start	End
ENSE00001459237	38885807	38886683
ENSE00001459240	38941682	38941830
ENSE00003888903	38893164	38893224
ENSE00003890982	38887963	38888024
ENSE00003892180	38918967	38919337
ENSE00003895682	38895969	38896069
ENSE00003895969	38911322	38911434
ENSE00003896005	38915562	38915710

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 88.09.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3509 / max 217.0966, expressed in 321 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11847	0.8406	146
11849	0.4177	170
11846	0.0927	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	88.09	gold quality
lower esophagus mucosa	UBERON:0035834	87.33	gold quality
colonic mucosa	UBERON:0000317	86.53	gold quality
rectum	UBERON:0001052	86.48	gold quality
esophagus mucosa	UBERON:0002469	85.71	gold quality
mucosa of transverse colon	UBERON:0004991	85.48	gold quality
esophagus squamous epithelium	UBERON:0006920	84.58	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.85	gold quality
spinal cord	UBERON:0002240	81.86	gold quality
skin of leg	UBERON:0001511	80.91	gold quality
skin of abdomen	UBERON:0001416	80.13	gold quality
oral cavity	UBERON:0000167	80.04	gold quality
zone of skin	UBERON:0000014	79.90	gold quality
corpus callosum	UBERON:0002336	78.39	gold quality
nasal cavity epithelium	UBERON:0005384	78.25	gold quality
palpebral conjunctiva	UBERON:0001812	77.66	gold quality
buccal mucosa cell	CL:0002336	77.51	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	77.47	gold quality
medial globus pallidus	UBERON:0002477	77.20	gold quality
substantia nigra	UBERON:0002038	76.17	gold quality
vagina	UBERON:0000996	75.74	gold quality
transverse colon	UBERON:0001157	75.08	gold quality
nasal cavity mucosa	UBERON:0001826	74.71	gold quality
minor salivary gland	UBERON:0001830	74.70	gold quality
colonic epithelium	UBERON:0000397	74.62	gold quality
inferior vagus X ganglion	UBERON:0005363	74.45	gold quality
midbrain	UBERON:0001891	74.39	gold quality
mouth mucosa	UBERON:0003729	74.19	gold quality
globus pallidus	UBERON:0001875	74.14	gold quality
putamen	UBERON:0001874	72.79	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	16.12
E-ANND-3	yes	10.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting RHBDL2, 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-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-670-3P	99.03	68.88	2404

Literature-anchored findings (GeneRIF, showing 7)

• Substrate specificity of RHBDL2 intramembrane protease is governed by helix-breaking residues in the transmembrane domain. (PMID:12820957)
• The encoded protein is thought to release soluble growth factors by proteolytic cleavage of certain membrane-bound substrates, including ephrin B2 and ephrin B3. (PMID:15047175)
• Here, the authors show that RHBDL2 is produced as a proenzyme and that the processing of RHBDL2 is required for its cellular protease activity. (PMID:19850051)
• RHBDL2 cleaves epidermal growth factor just outside its transmembrane domain, thereby facilitating its secretion and triggering activation of the epidermal growth factor receptor. (PMID:21494248)
• Thrombomodulin and RHBDL2 are upregulated in human HaCaT cells stimulated by scratch wounds; furthermore, increased solulbe thrombomodulin was found in culture medium. (PMID:21833011)
• Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling. (PMID:33566379)
• Rhomboid-like 2 correlated with TME infiltration inhibits cuproptosis-related genes and drives malignant phenotype in clear cell renal cell carcinoma. (PMID:39511359)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rhbdl2	ENSDARG00000069833
mus_musculus	Rhbdl2	ENSMUSG00000043333
rattus_norvegicus	Rhbdl2	ENSRNOG00000026592
drosophila_melanogaster	rho-5	FBGN0041723
caenorhabditis_elegans		WBGENE00004402
caenorhabditis_elegans		WBGENE00004403

Paralogs (5): RHBDF1 (ENSG00000007384), RHBDL1 (ENSG00000103269), RHBDF2 (ENSG00000129667), RHBDL3 (ENSG00000141314), PARL (ENSG00000175193)

Protein

Protein identifiers

Rhomboid-related protein 2 — Q9NX52 (reviewed: Q9NX52)

Alternative names: Rhomboid-like protein 2

All UniProt accessions (1): Q9NX52

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Known substrate: EFNB3.

Subcellular location. Cell membrane.

Post-translational modifications. Proteolytic processing of the proenzyme produces a N-terminal fragment (NTF) and a C-terminal fragment (CTF). The processing is required for activation of the protease.

Miscellaneous. May be due to an intron retention.

Similarity. Belongs to the peptidase S54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NX52-1	1	yes
Q9NX52-3	2

RefSeq proteins (2): NP_001291675, NP_060291* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017213	Peptidase_S54_rhomboid_met	Family
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily
IPR051739	Rhomboid_IM_Serine_Proteases	Family

Pfam: PF01694

Enzyme classification (BRENDA):

• EC 3.4.21.105 — rhomboid protease (BRENDA: 42 organisms, 229 substrates, 68 inhibitors, 19 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BODIPY FL CASEIN	0.0007–0.0029	12
FL-CASEIN	0.0018–0.0065	3
TATA	0.0076–0.119	3
CYPET-TATA-YPET	0.0039	1

UniProt features (22 total): transmembrane region 7, mutagenesis site 6, chain 3, active site 2, region of interest 1, compositionally biased region 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX52-F1	85.58	0.50

Functional residue map

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

Catalytic / active sites (2): 187 (nucleophile); 250

Mutagenesis-validated functional residues (6):

Position	Phenotype
121	reduces protease activity.
122	abolishes protease activity, prevents processing and alters localization to the plasma membrane of n-terminal fragment.
139	reduces protease activity.
185	abolishes protease activity.
187	abolishes protease activity.
250	abolishes protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 54 (showing top): chr1p34, NUYTTEN_EZH2_TARGETS_DN, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_DN, LIN_SILENCED_BY_TUMOR_MICROENVIRONMENT, MIKKELSEN_ES_ICP_WITH_H3K4ME3, CHICAS_RB1_TARGETS_CONFLUENT, ANDERSEN_CHOLANGIOCARCINOMA_CLASS2, MYC_UP.V1_DN, GSE13522_CTRL_VS_T_CRUZI_Y_STRAIN_INF_SKIN_129_MOUSE_DN, MIR12136, MIR4310, MIR519D_5P, MIR7157_5P

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHBDL2	NCSTN	Q92542	886
RHBDL2	PSENEN	Q9NZ42	845
RHBDL2	EFNB3	Q15768	839
RHBDL2	APH1A	Q96BI3	831
RHBDL2	EFNB2	P52799	717
RHBDL2	PSEN1	P49768	700
RHBDL2	HM13	Q8TCT9	617
RHBDL2	BACE1	P56817	572
RHBDL2	APP	P05067	571
RHBDL2	RHBDD1	Q8TEB9	570
RHBDL2	RHBDD2	Q6NTF9	567
RHBDL2	PARL	Q9H300	565
RHBDL2	A0A1W2PP11	A0A1W2PP11	564
RHBDL2	APH1B	Q8WW43	515
RHBDL2	GSTCD	Q8NEC7	487

IntAct

3 interactions, top by confidence:

A	B	Type	Score
RHBDL2	H1-2	psi-mi:“MI:0915”(physical association)	0.400
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): RHBDL2 (Synthetic Lethality), EFNB3 (Biochemical Activity), RHBDL2 (Two-hybrid), SLC35B4 (Two-hybrid), RHBDL2 (Proximity Label-MS), NOTCH1 (Affinity Capture-MS), NOTCH1 (Affinity Capture-Western), RHBDL2 (Affinity Capture-Western), RHBDL2 (Affinity Capture-Western), OTUD7B (Affinity Capture-Western), RHBDL2 (Affinity Capture-MS)

ESM2 similar proteins: A0AAS4, A2AGA4, A2AJN7, A2AWR3, F4JBM4, O14495, O42153, O82756, P20350, P58872, P58873, P70553, P97544, Q0WQX7, Q12270, Q19821, Q3SZE3, Q3TWI9, Q4JM44, Q4R763, Q4V3B8, Q53P98, Q58EK4, Q5R9A7, Q5T3F8, Q695T9, Q6NLA5, Q7T3T4, Q7TSX5, Q7Z3F1, Q810K3, Q86VZ5, Q8IWX5, Q8LF05, Q8NBS3, Q8NHU3, Q8RXW0, Q8VC82, Q8VCQ6, Q8VZ48

Diamond homologs: A0JPA1, A7YWH9, A9L8T6, B0VX73, B1MT31, C8VCL5, F4JBM4, O82756, P54493, Q00M95, Q0WQX7, Q499S9, Q695T8, Q695U0, Q6GMF8, Q6GV23, Q6IUY1, Q6PIX5, Q6PJF5, Q76NQ1, Q80WQ6, Q8VZ48, Q96CC6, Q9CAN1, Q9NX52, Q9SSR0, A2AGA4, A4WFK8, O75783, O88779, P20350, P34356, P58872, P58873, Q19821, Q8VC82, Q9LYP1, F4I8K2, P46116, P96617

SIGNOR signaling

0 interactions.

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	42
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1396 predictions. Top by Δscore:

Variant	Effect	Δscore
1:38893162:A:AC	donor_gain	1.0000
1:38893163:C:CC	donor_gain	1.0000
1:38893167:T:C	donor_gain	1.0000
1:38893222:ATTC:A	acceptor_loss	1.0000
1:38893223:TT:T	acceptor_gain	1.0000
1:38893224:TCT:T	acceptor_loss	1.0000
1:38893225:C:CA	acceptor_loss	1.0000
1:38893225:C:CC	acceptor_gain	1.0000
1:38893226:T:C	acceptor_gain	1.0000
1:38893226:T:TC	acceptor_gain	1.0000
1:38895916:A:AC	donor_gain	1.0000
1:38895917:C:CC	donor_gain	1.0000
1:38941680:AC:A	donor_gain	1.0000
1:38941681:CC:C	donor_gain	1.0000
1:38888020:CACAA:C	acceptor_gain	0.9900
1:38888022:CAA:C	acceptor_gain	0.9900
1:38888025:C:CC	acceptor_gain	0.9900
1:38893158:ACTT:A	donor_loss	0.9900
1:38893160:TTAC:T	donor_loss	0.9900
1:38893161:T:TC	donor_loss	0.9900
1:38893162:A:C	donor_loss	0.9900
1:38893163:CTTAT:C	donor_gain	0.9900
1:38893220:AAATT:A	acceptor_gain	0.9900
1:38893221:AATT:A	acceptor_gain	0.9900
1:38893222:ATT:A	acceptor_gain	0.9900
1:38911433:CT:C	acceptor_gain	0.9900
1:38941677:CTTAC:C	donor_loss	0.9900
1:38941678:TTACC:T	donor_loss	0.9900
1:38941679:TA:T	donor_loss	0.9900
1:38941680:A:AC	donor_gain	0.9900

AlphaMissense

1996 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:38918976:G:C	S79R	1.000
1:38918976:G:T	S79R	1.000
1:38918978:T:G	S79R	1.000
1:38886646:C:T	G257E	0.998
1:38911322:C:A	G170W	0.998
1:38911333:C:T	G166E	0.998
1:38911334:C:G	G166R	0.998
1:38911334:C:T	G166R	0.998
1:38915596:A:G	W121R	0.998
1:38915596:A:T	W121R	0.998
1:38915699:A:C	F86L	0.998
1:38915699:A:T	F86L	0.998
1:38915701:A:G	F86L	0.998
1:38886634:C:T	G261D	0.997
1:38896003:G:T	A192D	0.997
1:38896024:C:T	G185E	0.997
1:38911391:C:G	G147R	0.997
1:38911413:A:C	N139K	0.997
1:38911413:A:T	N139K	0.997
1:38886647:C:G	G257R	0.996
1:38886647:C:T	G257R	0.996
1:38886658:C:T	G253D	0.996
1:38895995:C:G	G195R	0.996
1:38895995:C:T	G195R	0.996
1:38896000:A:G	L193P	0.996
1:38896025:C:G	G185R	0.996
1:38896025:C:T	G185R	0.996
1:38896063:A:G	L172P	0.996
1:38886649:G:T	A256D	0.995
1:38895991:C:T	G196D	0.995

dbSNP variants (sampled 300 via entrez): RS1000057518 (1:38937332 T>C), RS1000062621 (1:38917345 A>G), RS1000093054 (1:38902641 C>T), RS1000204716 (1:38905145 A>C,G), RS1000291755 (1:38940231 G>A), RS1000318106 (1:38904988 G>A,T), RS1000370943 (1:38937630 T>C), RS1000407606 (1:38940474 T>G), RS1000480154 (1:38899220 A>T), RS1000601993 (1:38912485 T>C), RS1000625752 (1:38941592 C>T), RS1000658032 (1:38906299 T>C), RS1000671936 (1:38911318 T>C), RS1000673089 (1:38906390 A>C,G), RS1000738312 (1:38941766 G>A,T)

Disease associations

OMIM: gene MIM:608962 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001381_9	Menopause (age at onset)	9.000000e-17
GCST003475_2	Beard thickness	8.000000e-06
GCST005312_27	Menopause (age at onset)	5.000000e-21
GCST008528_2	Sweet beverage consumption	2.000000e-06
GCST010244_344	Triglyceride levels	3.000000e-08
GCST90026412_10	Severe autoimmune type 2 diabetes	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0010090	sweet beverage consumption measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	5
Tetrachlorodibenzodioxin	decreases expression	3
Cyclosporine	decreases expression	3
Aflatoxin B1	increases expression, increases methylation	3
OTX015	decreases expression	1
mivebresib	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
afimoxifene	decreases reaction, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Cadmium	increases abundance, increases expression	1
Estrogens	decreases expression, decreases reaction	1
Fluorouracil	affects response to substance	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	increases methylation	1
Quercetin	decreases expression	1
Silicon Dioxide	decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

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