IL22RA2

Summary

IL22RA2 (interleukin 22 receptor subunit alpha 2, HGNC:14901) is a protein-coding gene on chromosome 6q23.3, encoding Interleukin-22 receptor subunit alpha-2 (Q969J5). Isoform 2 is a receptor for IL22.

This gene encodes a member of the class II cytokine receptor family. The encoded soluble protein specifically binds to and inhibits interleukin 22 activity by blocking the interaction of interleukin 22 with its cell surface receptor. The encoded protein may be important in the regulation of inflammatory response, and has been implicated in the regulation of tumorigenesis in the colon. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 116379 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 35 total — 1 pathogenic
• MANE Select transcript: NM_052962

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14901
Approved symbol	IL22RA2
Name	interleukin 22 receptor subunit alpha 2
Location	6q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CRF2-S1, IL-22BP
Ensembl gene	ENSG00000164485
Ensembl biotype	protein_coding
OMIM	606648
Entrez	116379

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000296980, ENST00000339602, ENST00000349184

RefSeq mRNA: 3 — MANE Select: NM_052962 NM_052962, NM_181309, NM_181310

CCDS: CCDS5182, CCDS5183, CCDS5184

Canonical transcript exons

ENST00000296980 — 7 exons

Exon	Start	End
ENSE00001084681	137158347	137158482
ENSE00001084683	137156759	137156854
ENSE00001084686	137154941	137155119
ENSE00001084687	137147722	137147891
ENSE00001376683	137161689	137161814
ENSE00003712819	137143820	137145773
ENSE00003892773	137173413	137173644

Expression profiles

Bgee: expression breadth broad, 39 present calls, max score 64.19.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1752 / max 61.7473, expressed in 28 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75812	0.1692	25
75813	0.0061	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vermiform appendix	UBERON:0001154	64.19	gold quality
epithelium of nasopharynx	UBERON:0001951	63.58	gold quality
buccal mucosa cell	CL:0002336	62.16	silver quality
lower lobe of lung	UBERON:0008949	59.69	silver quality
caecum	UBERON:0001153	58.98	gold quality
lymph node	UBERON:0000029	57.95	gold quality
tendon of biceps brachii	UBERON:0008188	57.46	gold quality
tibialis anterior	UBERON:0001385	57.26	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
skin of hip	UBERON:0001554	54.06	silver quality
pancreatic ductal cell	CL:0002079	54.03	silver quality
epithelial cell of pancreas	CL:0000083	53.93	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
ileal mucosa	UBERON:0000331	52.92	silver quality
rectum	UBERON:0001052	50.55	gold quality
placenta	UBERON:0001987	50.36	gold quality
myocardium	UBERON:0002349	50.25	gold quality
deltoid	UBERON:0001476	50.10	gold quality
tonsil	UBERON:0002372	48.89	gold quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality
quadriceps femoris	UBERON:0001377	46.81	gold quality
cerebellar vermis	UBERON:0004720	46.54	gold quality
palpebral conjunctiva	UBERON:0001812	45.43	silver quality
vastus lateralis	UBERON:0001379	45.40	gold quality
duodenum	UBERON:0002114	44.70	gold quality
mammary gland	UBERON:0001911	44.15	gold quality
thoracic mammary gland	UBERON:0005200	44.13	gold quality
gall bladder	UBERON:0002110	44.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting IL22RA2, 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-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
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-5011-5P	100.00	83.46	5820
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3658	99.96	73.87	4379

Literature-anchored findings (GeneRIF, showing 21)

• The IL-22R and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces contributed mostly by helices A, D, and F and loop AB. (PMID:18675824)
• Crystallization and preliminary X-ray diffraction results of the IL-22-IL-22 binding protein (IL-22BP) complex are described. (PMID:19193995)
• Comparison of IL-22/IL-22BP and IL-22/IL-22R1 crystal structures shows that both receptors display an overlapping IL-22 binding surface, which is consistent with the inhibitory role played by IL-22 binding protein. (PMID:19285080)
• Polymorphisms in IL22RA1 are associated with severe CRS. (PMID:19393422)
• Through a combined approach including genetic and immunological investigation in an animal model and large-scale association studies of patients with multiple sclerosis (MS), IL-22RA2 is established as an MS risk gene. (PMID:21041731)
• IL-22BP is produced by eosinophils in the gut and blocks IL-22 protective actions in colitis. (PMID:26329427)
• The deletion of IFNGR1 causes complete IFN-gammaR1 deficiency. Despite the deletion ending very close to the IL22RA2 gene, it does not appear to affect IL22RA2 transcription. (PMID:26931784)
• expression higher in the epidermal compartment of the skin in comparison with dermis in both healthy skin and psoriasis skin (PMID:27676439)
• suggest that the human IL-22BP isoforms have distinct spatial and temporal roles and coordinately fine-tune IL-22-dependent STAT3 responses in tissues as a type of rheostat. (PMID:27678220)
• thia study shows shows that nonaffected skin of psoriasis patients displays lower expression of IL-22BP than skin of healthy controls, and that the strong IL-22 increase in lesional psoriatic skin is accompanied by a moderate induction of IL-22BP (PMID:28356382)
• IL-22BP expression was downregulated in skin biopsies of psoriasis patients compared to the skin of healthy donors. (PMID:29572462)
• Upon silencing of interleukin 22 receptor subunit alpha 2 (IL22RA2) expression in immature dendritic cells (moDC), molecular chaperone GRP78 (GRP78) levels were significantly reduced, suggesting that native IL22RA2 expression naturally contributes to upregulating GRP78 levels in these cells. (PMID:30619294)
• Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization (PMID:31292217)
• The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis. (PMID:31936765)
• Elevated IL-22 in psoriasis plays an anti-apoptotic role in keratinocytes through mediating Bcl-xL/Bax. (PMID:32632545)
• Low Interleukin-22 Binding Protein Is Associated With High Mortality in Alcoholic Hepatitis and Modulates Interleukin-22 Receptor Expression. (PMID:32955203)
• The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies. (PMID:33851257)
• Liver expression of IL-22, IL-22R1 and IL-22BP in patients with chronic hepatitis C with different fibrosis stages. (PMID:34920229)
• Down-regulating Interleukin-22/Interleukin-22 binding protein axis promotes inflammation and aggravates diet-induced metabolic disorders. (PMID:36108991)
• IL-22BP production is heterogeneously distributed in Crohn’s disease. (PMID:36311796)
• Circulating apelin, IL22RA2 and VEGF in pre-capillary pulmonary hypertension. (PMID:37975916)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il22ra2	ENSMUSG00000039760
rattus_norvegicus	Il22ra2	ENSRNOG00000012259

Paralogs (11): IL20RA (ENSG00000016402), IFNGR1 (ENSG00000027697), IL10RA (ENSG00000110324), F3 (ENSG00000117525), IFNAR1 (ENSG00000142166), IL22RA1 (ENSG00000142677), IFNAR2 (ENSG00000159110), IFNGR2 (ENSG00000159128), IL20RB (ENSG00000174564), IFNLR1 (ENSG00000185436), IL10RB (ENSG00000243646)

Protein

Protein identifiers

Interleukin-22 receptor subunit alpha-2 — Q969J5 (reviewed: Q969J5)

Alternative names: Cytokine receptor class-II member 10, Cytokine receptor family 2 member 10, Cytokine receptor family type 2, soluble 1, Interleukin-22-binding protein, ZcytoR16

All UniProt accessions (1): Q969J5

UniProt curated annotations — full annotation on UniProt →

Function. Isoform 2 is a receptor for IL22. Binds to IL22, prevents interaction with the functional IL-22R complex and blocks the activity of IL22 (in vitro). May play an important role as an IL22 antagonist in the regulation of inflammatory responses. Isoform 1 may play a role in establishing and maintaining successful pregnancy.

Subcellular location. Secreted.

Tissue specificity. Expressed in placenta, spleen, breast, skin and lung. Also detected in intestinal tract, testis, brain, heart and thymus. No expression found in prostate, bladder, kidney, ovary, muscle, bone marrow, liver and uterus. Isoform 1 is expressed only in placenta. Isoform 2 is expressed in placenta and breast and at lower level in spleen, skin, thymus and stomach.

Similarity. Belongs to the type II cytokine receptor family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q969J5-1	1, Long, CRF2-10L, CRF2-s1-long	yes
Q969J5-2	2, Short, CRF2-10, CRF2-s1-short
Q969J5-3	3, CRF2-10S

RefSeq proteins (3): NP_443194, NP_851826, NP_851827 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015373	Interferon/interleukin_rcp_dom	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050650

Pfam: PF01108, PF09294

UniProt features (35 total): strand 11, glycosylation site 5, helix 4, splice variant 3, domain 3, disulfide bond 2, sequence variant 2, site 2, signal peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3G9V	X-RAY DIFFRACTION	2.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969J5-F1	78.96	0.51

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): 99 (critical for il22-binding); 151 (critical for il22-binding)

Disulfide bonds (2): 110–118, 238–259

Glycosylation sites (5): 192, 209, 56, 166, 171

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8854691	Interleukin-20 family signaling

MSigDB gene sets: 75 (showing top): REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_8D_UP, KEGG_JAK_STAT_SIGNALING_PATHWAY, GOCC_RECEPTOR_COMPLEX, GOMF_CYTOKINE_BINDING

GO Biological Process (3): cytokine-mediated signaling pathway (GO:0019221), negative regulation of inflammatory response (GO:0050728), interleukin-22-mediated signaling pathway (GO:0140865)

GO Molecular Function (4): cytokine receptor activity (GO:0004896), interleukin-22 binding (GO:0042017), interleukin-22 receptor activity (GO:0042018), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	2
cytokine binding	2
cellular anatomical structure	2
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
transmembrane signaling receptor activity	1
immune receptor activity	1
cytokine receptor activity	1
interleukin-22 binding	1
interleukin-22-mediated signaling pathway	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

765 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL22RA2	IL22	Q9GZX6	969
IL22RA2	IL10RB	Q08334	780
IL22RA2	REG3G	Q6UW15	756
IL22RA2	IFNL3	Q8IZI9	733
IL22RA2	IFNL1	Q8IU54	707
IL22RA2	IFNLR1	Q8IU57	693
IL22RA2	IL10RA	Q13651	660
IL22RA2	IL26	Q9NPH9	626
IL22RA2	IFNL2	Q8IZJ0	626
IL22RA2	IL19	Q9UHD0	622
IL22RA2	IL24	Q13007	611
IL22RA2	STAT3	P40763	576
IL22RA2	IFNGR1	P15260	566
IL22RA2	IL22RA1	Q8N6P7	545
IL22RA2	IL20RB	Q6UXL0	541

IntAct

3 interactions, top by confidence:

A	B	Type	Score
IL22RA2	PTPRF	psi-mi:“MI:0914”(association)	0.350
IL22RA2	HSPA12A	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): TBC1D31 (Affinity Capture-MS), IL22RA2 (Reconstituted Complex), SP1 (Positive Genetic), IL22RA2 (Negative Genetic), STAT3 (Negative Genetic), OS9 (Affinity Capture-MS), DDX19B (Affinity Capture-MS), SYVN1 (Affinity Capture-MS), ART5 (Affinity Capture-MS), UBE2J1 (Affinity Capture-MS), PTPRF (Affinity Capture-MS), FAM8A1 (Affinity Capture-MS), IL17RA (Affinity Capture-MS), PRPS1L1 (Affinity Capture-MS), GAS6 (Affinity Capture-MS)

ESM2 similar proteins: K7NA32, K7NAJ3, O09030, O70458, O70535, P14753, P16310, P17181, P19235, P21183, P22272, P22273, P24055, P26955, P31785, P33896, P34902, P40190, P40223, P40321, P42701, P42702, P42703, P78552, Q00560, Q04790, Q07303, Q28589, Q5XNR9, Q60837, Q65Z14, Q6PHB0, Q6UXL0, Q764M8, Q7TNI4, Q80XF5, Q8K5B1, Q8MJS1, Q8NI17, Q95118

Diamond homologs: K9JA28, Q3SYS8, Q7TNI4, Q80XF5, Q80XZ4, Q8N6P7, Q969J5, Q61727, Q6PHB0, Q9UHF4, P15260, Q04790, Q08334, Q28589

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IL22	down-regulates	IL22RA2	binding
IL22RA2	up-regulates	IL22	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	28
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
830657	NC_000006.11:g.(?136482728)(137540520_?)del	Pathogenic

SpliceAI

1097 predictions. Top by Δscore:

Variant	Effect	Δscore
6:137154939:A:AC	donor_gain	1.0000
6:137154940:C:CC	donor_gain	1.0000
6:137154942:TTCCC:T	donor_gain	0.9900
6:137154943:T:A	donor_gain	0.9900
6:137156762:G:C	donor_gain	0.9900
6:137161815:C:CC	acceptor_gain	0.9900
6:137145774:C:CC	acceptor_gain	0.9800
6:137147892:C:CC	acceptor_gain	0.9800
6:137154939:ACTTT:A	donor_gain	0.9800
6:137154940:CTTTC:C	donor_gain	0.9800
6:137154941:TTTCC:T	donor_gain	0.9800
6:137156761:A:AC	donor_gain	0.9800
6:137156761:AG:A	donor_gain	0.9800
6:137145771:CTC:C	acceptor_gain	0.9700
6:137154940:CTTT:C	donor_gain	0.9700
6:137155027:T:TA	donor_gain	0.9700
6:137156761:AGC:A	donor_gain	0.9700
6:137147887:TTTTG:T	acceptor_gain	0.9600
6:137147889:TTG:T	acceptor_gain	0.9600
6:137152997:C:CT	acceptor_gain	0.9600
6:137152997:C:T	acceptor_gain	0.9600
6:137152998:A:T	acceptor_gain	0.9600
6:137147482:T:C	donor_gain	0.9500
6:137147888:TTTG:T	acceptor_gain	0.9500
6:137154928:C:CA	donor_gain	0.9500
6:137145772:TC:T	acceptor_gain	0.9400
6:137145773:CC:C	acceptor_gain	0.9400
6:137147890:TG:T	acceptor_gain	0.9400
6:137145779:C:CT	acceptor_gain	0.9300
6:137173408:CTTA:C	donor_loss	0.9300

AlphaMissense

1743 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:137155101:C:A	W104C	0.993
6:137155101:C:G	W104C	0.993
6:137154957:G:C	F152L	0.990
6:137154957:G:T	F152L	0.990
6:137154959:A:G	F152L	0.990
6:137158403:C:A	W47C	0.987
6:137158403:C:G	W47C	0.987
6:137154977:A:G	W146R	0.986
6:137154977:A:T	W146R	0.986
6:137155103:A:G	W104R	0.985
6:137155103:A:T	W104R	0.985
6:137154958:A:G	F152S	0.982
6:137155060:C:G	C118S	0.982
6:137155061:A:T	C118S	0.982
6:137154975:C:A	W146C	0.981
6:137154975:C:G	W146C	0.981
6:137155054:A:G	L120P	0.981
6:137158410:A:G	L45S	0.979
6:137158405:A:G	W47R	0.978
6:137158405:A:T	W47R	0.978
6:137158437:A:G	F36S	0.976
6:137155060:C:T	C118Y	0.974
6:137158356:T:G	Q63P	0.974
6:137147753:C:G	R204P	0.972
6:137154958:A:C	F152C	0.972
6:137155015:C:T	G133E	0.972
6:137158436:A:C	F36L	0.972
6:137158436:A:T	F36L	0.972
6:137158438:A:G	F36L	0.972
6:137155061:A:G	C118R	0.968

dbSNP variants (sampled 300 via entrez): RS1000039285 (6:137144148 G>A), RS1000131507 (6:137143607 G>A,T), RS1000214619 (6:137150301 G>A), RS1000238263 (6:137149807 T>G), RS1000276071 (6:137169588 G>A,C), RS1000304817 (6:137161673 GAAAC>G), RS1000309353 (6:137150557 TC>T), RS1000418199 (6:137160623 A>G), RS1000547359 (6:137154508 G>A,T), RS1000549760 (6:137166350 G>A,T), RS1000604837 (6:137161250 A>G,T), RS1000629937 (6:137148064 A>G), RS1000681709 (6:137154268 C>T), RS1000698471 (6:137149590 C>T), RS1000916506 (6:137164511 C>T)

Disease associations

OMIM: gene MIM:606648 | disease phenotypes: MIM:209950

GenCC curated gene-disease

Mondo (1): immunodeficiency 27A (MONDO:0008856)

Orphanet (2): Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency (Orphanet:319569), Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency (Orphanet:99898)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001198_24	Multiple sclerosis	6.000000e-13
GCST005531_120	Multiple sclerosis	2.000000e-23

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — IL-10 receptor family

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
pirinixic acid	affects binding, decreases expression, increases activity	1
1,6-hexamethylene diisocyanate	increases methylation	1
butyraldehyde	decreases expression	1
1-aminomethylphosphonic acid	decreases expression	1
Glyphosate	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Nickel	increases expression	1
Sodium Selenite	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	affects expression	1

Clinical trials (associated diseases)

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