RNF31

Summary

RNF31 (ring finger protein 31, HGNC:16031) is a protein-coding gene on chromosome 14q12, encoding E3 ubiquitin-protein ligase RNF31 (Q96EP0). E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear (‘Met-1’-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. It is a selective cancer dependency (DepMap: 10.6% of cell lines).

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-DNA and protein-protein interactions. The encoded protein is the E3 ubiquitin-protein ligase component of the linear ubiquitin chain assembly complex. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55072 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 115 with autoinflammation (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 878 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.6% of screened cell lines
• MANE Select transcript: NM_017999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16031
Approved symbol	RNF31
Name	ring finger protein 31
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	ZIBRA, FLJ10111, FLJ23501, HOIP, Paul
Ensembl gene	ENSG00000092098
Ensembl biotype	protein_coding
OMIM	612487
Entrez	55072

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 22 protein_coding, 14 retained_intron, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000324103, ENST00000483895, ENST00000491351, ENST00000557878, ENST00000557991, ENST00000558452, ENST00000558634, ENST00000558907, ENST00000559071, ENST00000559260, ENST00000559275, ENST00000559308, ENST00000559438, ENST00000559449, ENST00000559491, ENST00000559533, ENST00000559583, ENST00000559719, ENST00000559882, ENST00000560071, ENST00000560342, ENST00000560631, ENST00000560754, ENST00000560787, ENST00000560875, ENST00000699882, ENST00000699883, ENST00000699884, ENST00000699885, ENST00000699886, ENST00000699887, ENST00000699888, ENST00000699889, ENST00000699890, ENST00000699891, ENST00000699892, ENST00000886640, ENST00000886641, ENST00000886642, ENST00000886643, ENST00000886644, ENST00000912694, ENST00000912695, ENST00000949516, ENST00000949517

RefSeq mRNA: 2 — MANE Select: NM_017999 NM_001310332, NM_017999

CCDS: CCDS41931, CCDS81792

Canonical transcript exons

ENST00000324103 — 21 exons

Exon	Start	End
ENSE00002574912	24150061	24150448
ENSE00003477656	24147976	24148122
ENSE00003496004	24160520	24160655
ENSE00003496037	24147498	24147890
ENSE00003506993	24148258	24148413
ENSE00003607653	24148642	24148701
ENSE00003647855	24149406	24149583
ENSE00003756503	24148801	24148876
ENSE00003977870	24155603	24155692
ENSE00003977877	24151786	24151992
ENSE00003977882	24159864	24159960
ENSE00003977889	24151485	24151670
ENSE00003977890	24160239	24160407
ENSE00003977894	24157898	24158011
ENSE00003977898	24158142	24158199
ENSE00003977899	24155157	24155330
ENSE00003977901	24157290	24157404
ENSE00003977902	24157520	24157638
ENSE00003977907	24150598	24150888
ENSE00003977911	24151131	24151379
ENSE00003977916	24155414	24155512

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.5294 / max 594.9924, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138995	30.0338	1819
138994	0.4956	255

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	96.79	gold quality
granulocyte	CL:0000094	96.77	gold quality
apex of heart	UBERON:0002098	95.80	gold quality
blood	UBERON:0000178	95.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.57	gold quality
right lobe of thyroid gland	UBERON:0001119	95.54	gold quality
adenohypophysis	UBERON:0002196	95.31	gold quality
metanephros cortex	UBERON:0010533	95.31	gold quality
pituitary gland	UBERON:0000007	95.17	gold quality
body of pancreas	UBERON:0001150	95.02	gold quality
left lobe of thyroid gland	UBERON:0001120	94.95	gold quality
right ovary	UBERON:0002118	94.86	gold quality
left uterine tube	UBERON:0001303	94.85	gold quality
thyroid gland	UBERON:0002046	94.77	gold quality
cortex of kidney	UBERON:0001225	94.67	gold quality
prostate gland	UBERON:0002367	94.66	gold quality
fundus of stomach	UBERON:0001160	94.50	gold quality
body of uterus	UBERON:0009853	94.48	gold quality
left adrenal gland cortex	UBERON:0035825	94.48	gold quality
skin of leg	UBERON:0001511	94.42	gold quality
upper lobe of left lung	UBERON:0008952	94.42	gold quality
leukocyte	CL:0000738	94.39	gold quality
zone of skin	UBERON:0000014	94.36	gold quality
tibial nerve	UBERON:0001323	94.33	gold quality
left ovary	UBERON:0002119	94.33	gold quality
right adrenal gland cortex	UBERON:0035827	94.33	gold quality
monocyte	CL:0000576	94.31	gold quality
minor salivary gland	UBERON:0001830	94.30	gold quality
right adrenal gland	UBERON:0001233	94.29	gold quality
saliva-secreting gland	UBERON:0001044	94.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, NR0B1, NR5A1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 36)

• ZIBRA was identified and its genomic organization, regulation, and expression studied in breast cancer cells. (PMID:15093743)
• RNF31 functions to stabilize DAX-1; RNF31 appears to be required for DAX-1 to repress transcription (PMID:19237537)
• analysis of differentially expressed genes indicates systemic role for SF-1 in adrenal cortex affecting differentiation, proliferation and steroidogenesis and establishes RNF31 as an important regulator of adrenal steroidogenesis (PMID:22427816)
• The study highlights the versatility and specificity of protein-protein interactions involving Ub-like domain (UBL) of HOIL-1L/the Ub-associated domain (UBA) of HOIP and their cognate proteins. (PMID:22430200)
• The data showed how HOIP combines a general RING-IBR-RING ubiquitin ligase mechanism with unique, ‘Linear ubiquitin chain Determining Domain’-dependent specificity for producing linear ubiquitin chains. (PMID:22863777)
• The HOIP component of the linear ubiquitin assembly complex catalyzes the formation of M1-polyubiquitin chains in response to interleukin-1. (PMID:23986494)
• target specificity toward NEMO is determined by multiple LUBAC components, whereas linear ubiquitin chain elongation is realized by a specific interplay between HOIP and ubiquitin. (PMID:24030825)
• crystal structure of the catalytic core of HOIP in its apo form and in complex with ubiquitin (PMID:24141947)
• RNF31, via stabilizing ESR1 levels, controls the transcription of estrogen-dependent genes linked to breast cancer cell proliferation. (PMID:24441041)
• Two rare germline polymorphisms affecting the LUBAC subunit RNF31 were identified and enriched among patients with activated B cell-like subtype of diffuse large B-cell lymphoma. (PMID:24491438)
• Phosphorylation of OTULIN prevents HOIP binding, whereas unphosphorylated OTULIN is part of the endogenous LUBAC complex. (PMID:24726323)
• HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex. (PMID:24726327)
• human HOIP is essential for the assembly and function of LUBAC, which includes HOIL-1, and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells (PMID:26008899)
• we identified BCL10 as a bona fide target of BCR-induced linear ubiquitylation and demonstrated an important role of the linear ubiquitin ligase HOIP in BCR-induced phosphorylation (PMID:26038114)
• RNF31 decreased p53 stability. RNF31 depletion caused cell cycle arrest and cisplatin-induced apoptosis in a p53-dependent manner. RNF31 associated with the p53/MDM2 complex, facilitating p53 polyubiquitination and degradation by stabilizing MDM2. (PMID:26148235)
• These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. (PMID:26231797)
• This study describes a novel posttranslational regulation of the HOIP-containing linear-ubiquitin-chain assembly complex (LUBAC)-mediated linear ubiquitination that is critical for specifically directing TLR4-mediated NF-kappaB activation. (PMID:26578682)
• crystal structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation (PMID:26789245)
• This review highlights recent discoveries on RNF31 functions in nuclear factor modifications, breast cancer progression and possible therapeutic inhibitors targeting RNF31. [review] (PMID:27460922)
• SPATA2 has been described as a previously unrecognized factor in the linear ubiquitin chain assembly complex-dependent signaling pathways that serves as an adaptor between HOIP and CYLD, thereby enabling recruitment of CYLD to signaling complexes. (PMID:27545878)
• The data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of linear ubiquitin chain assembly complex-mediated NF-kappaB signaling. (PMID:27591049)
• Study found that RNF31 is cleaved under apoptosis conditions through various stimulations; findings elucidate a novel regulatory loop between cell death and the survival signal (PMID:27669734)
• LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation. (PMID:27810922)
• These results indicate that caspase-mediated cleavage of HOIP divides critical functional regions of HOIP, and that this regulates linear (de)ubiquitination of substrates upon apoptosis. (PMID:28189684)
• The binding of SHARPIN or HOIL-1L facilitates the E2 loading of HOIP. (PMID:28978479)
• Human Treg cells that ectopically expressed RNF31 displayed stronger immune-suppressive capacity, suggesting that RNF31 positively regulates both FOXP3 stability and Treg cell function. (PMID:30389786)
• Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC. (PMID:30936877)
• Cross-regulation between LUBAC and caspase-1 modulates cell death and inflammation. (PMID:32122970)
• Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders. (PMID:32403254)
• Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling. (PMID:33215740)
• RNF31 mediated ubiquitination of A20 aggravates inflammation and hepatocyte apoptosis through the TLR4/MyD88/NF-kappaB signaling pathway. (PMID:34416243)
• Effects of removing a highly conserved disulfide bond in ubiquitin-associated domain of human HOIP on biochemical characteristics. (PMID:34695570)
• RNF31 represses cell progression and immune evasion via YAP/PD-L1 suppression in triple negative breast Cancer. (PMID:36581998)
• RNF31 promotes tumorigenesis via inhibiting RIPK1 kinase-dependent apoptosis. (PMID:36997719)
• Resonance assignments of the PUB domain of the RNF31 protein. (PMID:37395936)
• RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation. (PMID:38172174)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000090770
danio_rerio		ENSDARG00000113057
mus_musculus	Rnf31	ENSMUSG00000047098
rattus_norvegicus	Rnf31	ENSRNOG00000019438
drosophila_melanogaster	LUBEL	FBGN0031857

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF31 — Q96EP0 (reviewed: Q96EP0)

Alternative names: HOIL-1-interacting protein, RING finger protein 31, RING-type E3 ubiquitin transferase RNF31, Zinc in-between-RING-finger ubiquitin-associated domain protein

All UniProt accessions (16): Q96EP0, A0A8V8TPI3, A0A8V8TQD3, A0A8V8TQR2, H0YKI4, H0YKX0, H0YM13, H0YM57, H0YMG4, H0YMG8, H0YMK6, H0YMN0, H0YNC1, H0YNJ0, H0YNK5, H0YNT1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear (‘Met-1’-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria. LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin. Recruited to the surface of bacteria by RNF213, which initiates the bacterial ubiquitin coat. The bacterial ubiquitin coat acts as an ’eat-me’ signal for xenophagy and promotes NF-kappa-B activation. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. RNF31 is required for linear ubiquitination of BCL10, thereby promoting TCR-induced NF-kappa-B activation. Binds polyubiquitin of different linkage types.

Subunit / interactions. Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31. LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits. Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner. Interacts (via the PUB domain) with OTULIN (via the PIM motif); the interaction is direct. Interacts (via the PUB domain) with VCP (via the PIM motif). Interacts (via the PUB domain) with SPATA2 (via the PIM motif); interaction is direct and bridges RNF31 and CYLD. Interacts with CYLD; the interaction is indirect and is mediated via SPATA2. Interacts with MUSK. Interacts with CARD11, promoting linear ubiquitination of BCL10. (Microbial infection) Interacts with S.flexneri E3 ubiquitin-protein ligases IpaH1.4 and IpaH2.5, leading to its ubiquitination.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in both normal and transformed breast epithelial cell lines.

Post-translational modifications. Autoubiquitinated. Interaction with OTULIN is required to suppress formation of ‘Met-1’-linked polyubiquitin chains and prevent subsequent inactivation of the LUBAC complex. Cleaved by caspase during apoptosis. (Microbial infection) Ubiquitinated by S.flexneri E3 ubiquitin-protein ligases IpaH1.4 and IpaH2.5, leading to its degradation by the proteasome, thereby preventing formation of the bacterial ubiquitin coat and activation of innate immunity.

Disease relevance. Immunodeficiency 115 with autoinflammation (IMD115) [MIM:620632] An autosomal recessive immunologic disorder manifesting in early infancy and characterized by combined immunodeficiency, recurrent bacterial, viral, and fungal infections, as well as autoinflammatory features, including arthritis and dermatitis. The disease is caused by variants affecting the gene represented in this entry. The genetic variation producing the missense variant p.Q399H, associated with IMD115, has been shown to predominantly affect splicing, leading to in-frame skipping of exon 9 and lack of 84 amino acids from residue 496 to 579.

Domain organisation. The PUB domain mediates interaction with the PIM motifs of VCP and RNF31, with a strong preference for RNF31. The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. The UBA domain mediates association with RBCK1/HOIL1 via interaction with its UBL domain. RING 1 and IBR zinc-fingers catalyze the first step transfer of ubiquitin from the E2 onto RING 2, to transiently form a HECT-like covalent thioester intermediate. The linear ubiquitin chain determining domain (LDD) mediates the final transfer of ubiquitin from RING 2 onto the N-terminus of a target ubiquitin.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RBR family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96EP0-1	1	yes
Q96EP0-2	2
Q96EP0-3	3

RefSeq proteins (2): NP_001297261, NP_060469* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001876	Znf_RanBP2	Domain
IPR002867	IBR_dom	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR015940	UBA	Domain
IPR017907	Znf_RING_CS	Conserved_site
IPR018997	PUB_domain	Domain
IPR026254	RNF31-like	Family
IPR032065	RNF31-UBA	Domain
IPR036339	PUB-like_dom_sf	Homologous_superfamily
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR040641	RNF31_PUB	Domain
IPR041031	RNF31_C	Domain
IPR044066	TRIAD_supradom	Domain
IPR047539	UBA_RNF31	Domain
IPR047540	BRcat_RBR_RNF31-like	Domain
IPR047541	RNF31_RBR_mRING-HC-like	Domain
IPR047542	Rcat_RBR_RNF31-like	Domain
IPR047543	Bbox1_RNF31-like	Domain
IPR057426	RNF31_UBA_3	Domain

Pfam: PF09409, PF16678, PF18091, PF18486, PF22191, PF25163

Enzyme classification (BRENDA):

• EC 2.3.2.31 — RBR-type E3 ubiquitin transferase (BRENDA: 4 organisms, 35 substrates, 4 inhibitors, 0 Km, 0 kcat entries)

UniProt features (159 total): helix 36, binding site 24, strand 22, mutagenesis site 20, turn 18, region of interest 6, zinc finger region 6, sequence conflict 6, compositionally biased region 4, splice variant 4, cross-link 3, sequence variant 3, domain 2, modified residue 2, chain 1, active site 1, site 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6KC5	X-RAY DIFFRACTION	1.54
4LJO	X-RAY DIFFRACTION	1.56
7V8F	X-RAY DIFFRACTION	1.66
4P09	X-RAY DIFFRACTION	1.7
9B0B	X-RAY DIFFRACTION	1.7
9B12	X-RAY DIFFRACTION	1.81
4OWF	X-RAY DIFFRACTION	2
4OYK	X-RAY DIFFRACTION	2
6SC5	X-RAY DIFFRACTION	2.1
6SC8	X-RAY DIFFRACTION	2.11
6KC6	X-RAY DIFFRACTION	2.12
4LJP	X-RAY DIFFRACTION	2.15
6GZY	X-RAY DIFFRACTION	2.15
6SC6	X-RAY DIFFRACTION	2.25
8Z30	X-RAY DIFFRACTION	2.3
4P0A	X-RAY DIFFRACTION	2.3
7UYJ	X-RAY DIFFRACTION	2.32
4JUY	X-RAY DIFFRACTION	2.4
9B0Z	X-RAY DIFFRACTION	2.41
4LJQ	X-RAY DIFFRACTION	2.45
6SC9	X-RAY DIFFRACTION	2.47
7UY2	X-RAY DIFFRACTION	2.51
6SC7	X-RAY DIFFRACTION	2.56
8Z36	X-RAY DIFFRACTION	2.63
7UYK	X-RAY DIFFRACTION	2.7
4P0B	X-RAY DIFFRACTION	2.7
5LJN	X-RAY DIFFRACTION	2.7
4DBG	X-RAY DIFFRACTION	2.71
7V8G	X-RAY DIFFRACTION	2.75
9IIC	X-RAY DIFFRACTION	2.78

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EP0-F1	78.39	0.34

Antibody-complex structures (SAbDab): 5 — 6SC5, 6SC6, 6SC7, 6SC8, 6SC9

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): 885; 390–391 (cleavage; by caspase)

Ligand- & substrate-binding residues (24): 699; 702; 717; 719; 722; 725; 744; 747; 799; 802; 817; 820 …

Post-translational modifications (5): 383, 466, 735, 783, 875

Mutagenesis-validated functional residues (20):

Position	Phenotype
82	abolished interaction with otulin.
82	reduced interaction with otulin.
85	reduced interaction with otulin.
99	reduced interaction with otulin.
101	does not affect interaction with otulin.
102	abolished interaction with spata2.
102	abolished interaction with otulin.
104	reduced interaction with otulin.
360	decreased ubiquitin-binding and ability to promote formation of the bacterial ubiquitin coat.
390	abolishes cleavage by caspase.
699	abolishes polyubiquitination activity of lubac; when associated with s-702.
702	abolishes polyubiquitination activity of lubac; when associated with s-699.
735	reduced ubiquitination; when associated with r-783 and r-875.
783	reduced ubiquitination; when associated with r-735 and r-875.
871	abolishes polyubiquitination activity of lubac; when associated with s-874.
874	abolishes polyubiquitination activity of lubac; when associated with s-871.
875	reduced ubiquitination; when associated with r-735 and r-783.
885	abolished e3 ubiquitin-protein ligase activity and ability to promote formation of the bacterial ubiquitin coat; when as
935	abolished e3 ubiquitin-protein ligase activity and ability to promote formation of the bacterial ubiquitin coat; when as
983	abolished e3 ubiquitin-protein ligase activity and ability to promote formation of the bacterial ubiquitin coat; when as

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-162582	Signal Transduction
R-HSA-73887	Death Receptor Signaling
R-HSA-75893	TNF signaling

MSigDB gene sets: 265 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_REGULATION_OF_AUTOPHAGY, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_PROTEIN_TARGETING, GCAAGGA_MIR502, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_XENOPHAGY, chr14q12, GOBP_MACROAUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (14): protein polyubiquitination (GO:0000209), canonical NF-kappaB signal transduction (GO:0007249), CD40 signaling pathway (GO:0023035), defense response to bacterium (GO:0042742), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), T cell receptor signaling pathway (GO:0050852), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), negative regulation of necroptotic process (GO:0060546), protein linear polyubiquitination (GO:0097039), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), positive regulation of xenophagy (GO:1904417), cell surface receptor signaling pathway (GO:0007166), protein ubiquitination (GO:0016567)

GO Molecular Function (12): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), K48-linked polyubiquitin modification-dependent protein binding (GO:0036435), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), ubiquitin protein ligase activity (GO:0061630), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), linear polyubiquitin binding (GO:1990450), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): cytosol (GO:0005829), cytoplasmic side of plasma membrane (GO:0009898), CD40 receptor complex (GO:0035631), LUBAC complex (GO:0071797), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TNF signaling	3
Signal Transduction	1
Death Receptor Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
polyubiquitin modification-dependent protein binding	2
cellular anatomical structure	2
protein ubiquitination	1
intracellular signaling cassette	1
cell surface receptor signaling pathway	1
defense response	1
response to bacterium	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
antigen receptor-mediated signaling pathway	1
regulation of necroptotic process	1
negative regulation of programmed necrotic cell death	1
necroptotic process	1
protein polyubiquitination	1
positive regulation of macroautophagy	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
xenophagy	1
regulation of xenophagy	1
signal transduction	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
protein binding	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin binding	1
binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
plasma membrane	1
cytoplasmic side of membrane	1
plasma membrane signaling receptor complex	1
ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF31	RBCK1	Q9BYM8	998
RNF31	SHARPIN	Q9H0F6	998
RNF31	OTULIN	Q96BN8	916
RNF31	CYLD	Q9NQC7	909
RNF31	IKBKG	Q9Y6K9	888
RNF31	IREB2	P48200	885
RNF31	BIRC2	Q13490	864
RNF31	RIPK1	Q13546	823
RNF31	SPATA2	Q9UM82	778
RNF31	TRADD	Q15628	753
RNF31	IKBKB	O14920	705
RNF31	TRAF6	Q9Y4K3	678
RNF31	CHUK	O15111	677
RNF31	UBA1	P22314	671
RNF31	TRIM25	Q14258	670

IntAct

240 interactions, top by confidence:

A	B	Type	Score
RBCK1	RNF31	psi-mi:“MI:0914”(association)	0.980
RNF31	RBCK1	psi-mi:“MI:0914”(association)	0.980
RNF31	RBCK1	psi-mi:“MI:0915”(physical association)	0.980
RBCK1	RNF31	psi-mi:“MI:0915”(physical association)	0.980
RNF31	RBCK1	psi-mi:“MI:2364”(proximity)	0.980
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
RNF31	SHARPIN	psi-mi:“MI:0915”(physical association)	0.960
SHARPIN	RNF31	psi-mi:“MI:0914”(association)	0.960

BioGRID (795): PRKCA (Biochemical Activity), RNF31 (Two-hybrid), RNF31 (Two-hybrid), RNF31 (Two-hybrid), KRTAP9-2 (Two-hybrid), VASN (Two-hybrid), CCDC24 (Two-hybrid), UBE2D3 (Reconstituted Complex), IKBKG (Biochemical Activity), RNF31 (Affinity Capture-Western), IKBKG (Biochemical Activity), Sharpin (Affinity Capture-Western), RNF31 (Affinity Capture-Western), UBC (Biochemical Activity), UBE2D3 (Reconstituted Complex)

ESM2 similar proteins: A0A8P0N4K0, A2AB59, B4F7F3, D3YZU1, D3ZD05, O35681, O75427, O95382, P22455, P22607, P40748, P55144, P70218, Q06418, Q14160, Q1LZH7, Q2PS20, Q32P44, Q495M9, Q4ACU6, Q4H4B6, Q505F5, Q5F488, Q61851, Q63ZY3, Q6P9K8, Q6TLK4, Q6ZUM4, Q7KRY7, Q80T11, Q80U72, Q8BH60, Q8BX02, Q8N1G4, Q8TE68, Q8VC03, Q8VHK1, Q8VHK2, Q8WXD9, Q8WXE0

Diamond homologs: Q8IPJ3, Q924T7, Q96EP0

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RNF31	ubiquitination
RNF31	“form complex”	LUBAC	binding
RNF31	“up-regulates quantity by stabilization”	NR0B1	monoubiquitination
RNF31	“up-regulates activity”	IKBKG	polyubiquitination
RNF31	“up-regulates activity”	CASP1	polyubiquitination
CASP1	“down-regulates activity”	RNF31	cleavage
CASP8	“down-regulates activity”	RNF31	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 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
TNFR1-induced NF-kappa-B signaling pathway	12	47.4×	5e-15
Regulation of NF-kappa B signaling	6	44.8×	3e-07
TICAM1, RIP1-mediated IKK complex recruitment	6	42.4×	3e-07
TNF signaling	8	39.8×	3e-09
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	6	36.6×	8e-07
TNFR1-induced proapoptotic signaling	7	36.2×	7e-08
IKK complex recruitment mediated by RIP1	6	35.0×	1e-06
Regulation of TNFR1 signaling	12	31.6×	6e-13

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	12	36.0×	4e-13
tumor necrosis factor-mediated signaling pathway	7	19.0×	3e-05
obsolete positive regulation of NF-kappaB transcription factor activity	7	11.8×	4e-04
negative regulation of canonical NF-kappaB signal transduction	8	11.3×	1e-04
JNK cascade	5	11.1×	7e-03
protein K63-linked ubiquitination	5	11.0×	7e-03
positive regulation of canonical NF-kappaB signal transduction	16	9.5×	6e-09
positive regulation of JNK cascade	7	9.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	459
Likely benign	370
Benign	23

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
203412	NM_017999.5(RNF31):c.215T>C (p.Leu72Pro)	Pathogenic
2663901	NM_017999.5(RNF31):c.1197G>C (p.Gln399His)	Pathogenic
599586	NM_017999.5(RNF31):c.2333A>G (p.Tyr778Cys)	Likely pathogenic

SpliceAI

3160 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24147888:G:GT	donor_gain	1.0000
14:24147888:G:T	donor_gain	1.0000
14:24147888:GAGGT:G	donor_loss	1.0000
14:24147890:GGTG:G	donor_loss	1.0000
14:24147891:GTGAG:G	donor_loss	1.0000
14:24147967:T:TA	acceptor_gain	1.0000
14:24147970:TCCCA:T	acceptor_loss	1.0000
14:24147971:CCCAG:C	acceptor_loss	1.0000
14:24147972:CCAG:C	acceptor_loss	1.0000
14:24147973:CA:C	acceptor_loss	1.0000
14:24147974:A:AG	acceptor_gain	1.0000
14:24147974:A:AT	acceptor_loss	1.0000
14:24147975:G:GG	acceptor_gain	1.0000
14:24147975:GC:G	acceptor_gain	1.0000
14:24147975:GCC:G	acceptor_gain	1.0000
14:24147975:GCCC:G	acceptor_gain	1.0000
14:24147975:GCCCC:G	acceptor_gain	1.0000
14:24148074:TGTC:T	donor_gain	1.0000
14:24148118:TGCAG:T	donor_loss	1.0000
14:24148119:GCAGG:G	donor_loss	1.0000
14:24148120:CAGGT:C	donor_loss	1.0000
14:24148121:AGGTG:A	donor_loss	1.0000
14:24148122:GGTGA:G	donor_loss	1.0000
14:24148123:G:A	donor_loss	1.0000
14:24148124:T:G	donor_loss	1.0000
14:24148699:GAT:G	donor_gain	1.0000
14:24148702:G:GG	donor_gain	1.0000
14:24148707:G:GT	donor_gain	1.0000
14:24148708:A:T	donor_gain	1.0000
14:24148716:A:T	donor_gain	1.0000

AlphaMissense

6920 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24155495:T:C	F796L	1.000
14:24155497:C:A	F796L	1.000
14:24155497:C:G	F796L	1.000
14:24155504:T:C	C799R	1.000
14:24155648:T:C	C817R	1.000
14:24157522:T:C	C871R	1.000
14:24157579:T:C	C890R	1.000
14:24157581:T:G	C890W	1.000
14:24157600:T:C	F897L	1.000
14:24157602:C:A	F897L	1.000
14:24157602:C:G	F897L	1.000
14:24155256:T:C	C744R	0.999
14:24155496:T:C	F796S	0.999
14:24155501:T:A	W798R	0.999
14:24155501:T:C	W798R	0.999
14:24155503:G:C	W798C	0.999
14:24155503:G:T	W798C	0.999
14:24155504:T:A	C799S	0.999
14:24155505:G:A	C799Y	0.999
14:24155505:G:C	C799S	0.999
14:24155506:T:G	C799W	0.999
14:24155603:T:A	C802S	0.999
14:24155603:T:C	C802R	0.999
14:24155604:G:C	C802S	0.999
14:24155605:C:G	C802W	0.999
14:24155613:G:A	G805D	0.999
14:24155649:G:A	C817Y	0.999
14:24155650:T:G	C817W	0.999
14:24155672:T:C	C825R	0.999
14:24155673:G:A	C825Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000044519 (14:24155356 G>A,C), RS1000376568 (14:24154054 C>T), RS1000727801 (14:24146254 A>G), RS1000943858 (14:24150375 G>A,C), RS1001120646 (14:24158912 A>G), RS1001574712 (14:24147343 G>A,C,T), RS1001833316 (14:24145798 G>A), RS1002188954 (14:24156457 C>G,T), RS1002386876 (14:24156868 G>C), RS1002672305 (14:24153180 C>G,T), RS1002724130 (14:24149744 G>A), RS1002753537 (14:24149428 C>T), RS1003065190 (14:24153760 C>A,T), RS1003281008 (14:24154425 A>G), RS1003446728 (14:24153511 A>T)

Disease associations

OMIM: gene MIM:612487 | disease phenotypes: MIM:620632, MIM:615895

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 115 with autoinflammation	Moderate	Autosomal recessive
autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 115 with autoinflammation	Moderate	AR

Mondo (3): immunodeficiency 115 with autoinflammation (MONDO:0957981), polyglucosan body myopathy 1 with or without immunodeficiency (MONDO:0014389), autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis (MONDO:0017992)

Orphanet (2): Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis (Orphanet:329173), Polyglucosan body myopathy type 1 (Orphanet:397937)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000964	Eczematoid dermatitis
HP:0001217	Clubbing
HP:0001263	Global developmental delay
HP:0001744	Splenomegaly
HP:0001903	Anemia
HP:0001954	Recurrent fever
HP:0002254	Intermittent diarrhea
HP:0002593	Intestinal lymphangiectasia
HP:0002718	Recurrent bacterial infections
HP:0002721	Immunodeficiency
HP:0003073	Hypoalbuminemia
HP:0003202	Skeletal muscle atrophy
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004315	Decreased circulating IgG concentration
HP:0004429	Recurrent viral infections
HP:0005403	Decreased total T cell count
HP:0007340	Lower limb muscle weakness
HP:0008897	Postnatal growth retardation
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0012548	Fatty replacement of skeletal muscle
HP:0020180	Elevated haptoglobin level
HP:0031190	Superficial dermal perivascular inflammatory infiltrate
HP:0031402	Reduced antigen-specific T cell proliferation
HP:0032183	Decreased memory T cell proportion
HP:0032435	Neonatal omphalitis
HP:0033351	Candida esophagitis
HP:0040081	Abnormal circulating creatine kinase concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002969_3	Suicide behavior	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007623	suicide behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4296109 (PROTEIN COMPLEX), CHEMBL5465546 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.29	IC50	510	nM	GLIOTOXIN

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
(1R,7S,8S,11R)-7-hydroxy-11-(hydroxymethyl)-15-methyl-12,13-dithia-9,15-diazatetracyclo[9.2.2.01,9.03,8]pentadeca-3,5-diene-10,14-dione	1371346: Inhibition of petit-LUBAC (unknown origin)-mediated ubiquitylation expressed in Escherichia coli BL21 after 2 hrs in presence of E1, UbcH5c, E3 and ubiquitin	ic50	0.5100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
trichostatin A	affects expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate	decreases reaction, increases secretion	1
licochalcone B	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Benzene	decreases expression	1
Camptothecin	decreases response to substance	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	increases expression, increases secretion, affects reaction, increases reaction, decreases reaction	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4185513	Binding	Inhibition of petit-LUBAC (unknown origin)-mediated ubiquitylation expressed in Escherichia coli BL21 after 2 hrs in presence of E1, UbcH5c, E3 and ubiquitin	Interrogating the Roles of Post-Translational Modifications of Non-Histone Proteins. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TJ36	HAP1 RNF31 (-) 1	Cancer cell line	Male
CVCL_TJ37	HAP1 RNF31 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study