RBCK1

Summary

RBCK1 (RANBP2-type and C3HC4-type zinc finger containing 1, HGNC:15864) is a protein-coding gene on chromosome 20p13, encoding RanBP-type and C3HC4-type zinc finger-containing protein 1 (Q9BYM8). E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates.

Enables several functions, including identical protein binding activity; transcription coactivator activity; and ubiquitin binding activity. Involved in several processes, including positive regulation of canonical NF-kappaB signal transduction; protein linear polyubiquitination; and regulation of DNA-binding transcription factor activity. Part of LUBAC complex. Implicated in glycogen storage disease.

Source: NCBI Gene 10616 — RefSeq curated summary.

At a glance

• Gene–disease (curated): polyglucosan body myopathy 1 with or without immunodeficiency (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 579 total — 37 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• MANE Select transcript: NM_031229

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15864
Approved symbol	RBCK1
Name	RANBP2-type and C3HC4-type zinc finger containing 1
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	RBCK2, XAP4, RNF54, ZRANB4, UBCE7IP3, HOIL1
Ensembl gene	ENSG00000125826
Ensembl biotype	protein_coding
OMIM	610924
Entrez	10616

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 29 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000353660, ENST00000356286, ENST00000382181, ENST00000382214, ENST00000400245, ENST00000400247, ENST00000411647, ENST00000414880, ENST00000415942, ENST00000441733, ENST00000465226, ENST00000468272, ENST00000475269, ENST00000621487, ENST00000697804, ENST00000697805, ENST00000697807, ENST00000697808, ENST00000697809, ENST00000697810, ENST00000878594, ENST00000878595, ENST00000878596, ENST00000878597, ENST00000878598, ENST00000878599, ENST00000878600, ENST00000878601, ENST00000878602, ENST00000932273, ENST00000952169, ENST00000952170, ENST00000952171, ENST00000952172, ENST00000952173, ENST00000952174, ENST00000952175, ENST00000952176, ENST00000952177, ENST00000952178

RefSeq mRNA: 6 — MANE Select: NM_031229 NM_001323956, NM_001323958, NM_001323960, NM_001410770, NM_006462, NM_031229

CCDS: CCDS12998, CCDS13000, CCDS82587, CCDS92997

Canonical transcript exons

ENST00000356286 — 12 exons

Exon	Start	End
ENSE00000000072	408299	408779
ENSE00000000073	430350	432139
ENSE00001226965	420871	421031
ENSE00001621542	409881	410025
ENSE00003463684	427313	427492
ENSE00003465733	419558	419731
ENSE00003466139	428491	428589
ENSE00003495924	428951	429094
ENSE00003563959	419347	419468
ENSE00003564510	422127	422238
ENSE00003580941	417732	417930
ENSE00003693407	417526	417619

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 98.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.7014 / max 535.4932, expressed in 1826 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183048	38.9241	1823
183045	15.9897	1796
183049	6.3500	1547
183047	1.6791	969
183051	0.3436	141
183050	0.2507	115
183046	0.0573	18
183042	0.0266	12
183044	0.0238	7
183040	0.0229	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.72	gold quality
adenohypophysis	UBERON:0002196	98.53	gold quality
cerebellar hemisphere	UBERON:0002245	98.48	gold quality
cerebellar cortex	UBERON:0002129	98.28	gold quality
right uterine tube	UBERON:0001302	98.12	gold quality
right lobe of liver	UBERON:0001114	97.80	gold quality
granulocyte	CL:0000094	97.78	gold quality
right adrenal gland	UBERON:0001233	97.71	gold quality
left adrenal gland cortex	UBERON:0035825	97.59	gold quality
left adrenal gland	UBERON:0001234	97.55	gold quality
right adrenal gland cortex	UBERON:0035827	97.51	gold quality
metanephros cortex	UBERON:0010533	97.43	gold quality
right lobe of thyroid gland	UBERON:0001119	97.38	gold quality
lower esophagus mucosa	UBERON:0035834	97.37	gold quality
pituitary gland	UBERON:0000007	97.34	gold quality
mucosa of transverse colon	UBERON:0004991	97.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.33	gold quality
left lobe of thyroid gland	UBERON:0001120	97.30	gold quality
right ovary	UBERON:0002118	97.27	gold quality
apex of heart	UBERON:0002098	97.23	gold quality
left ovary	UBERON:0002119	97.23	gold quality
endocervix	UBERON:0000458	97.07	gold quality
spleen	UBERON:0002106	97.07	gold quality
transverse colon	UBERON:0001157	96.91	gold quality
upper lobe of left lung	UBERON:0008952	96.90	gold quality
body of uterus	UBERON:0009853	96.87	gold quality
body of stomach	UBERON:0001161	96.84	gold quality
adrenal cortex	UBERON:0001235	96.79	gold quality
ectocervix	UBERON:0012249	96.74	gold quality
tibial nerve	UBERON:0001323	96.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.96
E-CURD-112	no	2.55

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CCNB1	Activation
ESRRA	Activation

miRNA regulators (miRDB)

46 targeting RBCK1, 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-4692	100.00	67.32	2066
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-628-3P	99.04	68.37	814
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-5001-3P	98.91	67.28	1394

Literature-anchored findings (GeneRIF, showing 40)

• RBCK1 (human C20orf18 and rat Pkcbpb15) is involved in transcriptional machinery in the nuclear bodies, and its transcriptional activity is regulated by nucleocytoplasmic shuttling. (PMID:15833741)
• RBCK2 serves as a cytoplasmic tethering protein for RBCK1 (PMID:16083853)
• HOIL-1 expression stabilizes SOCS6 and induces the ubiquitination and degradation of proteins associated with SOCS6 (PMID:16643902)
• findings suggest that RBCK1 is involved in negative regulation of inflammatory signaling triggered by TNF and IL-1 through targeting TAB2/3 for degradation (PMID:17449468)
• These data demonstrate that HOIL-1 is not required for iron-dependent degradation of IRP2 in HEK293 cells, and suggest that a HOIL-1 independent mechanism is used for IRP2 degradation in most cell types. (PMID:17822790)
• the E3 activity of RBCK1 is controlled by two distinct manners, interaction with RBCK2 and phosphorylation by PKCbeta (PMID:18303026)
• Study shows that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) catalyzes the ubiquitination and degradation of IRF3. (PMID:18711448)
• The shRNA barcode screening technique identified RBCK1 as being involved in p53 regulation. (PMID:19277210)
• RBCK2 functions as an adaptor protein for the polyubiquitinated protein and the S5a subunit in 26S proteasome through its novel zinc finger motif and ubiquitin-like domain, respectively. (PMID:19796170)
• Findings suggest that RBCK1 regulates cell cycle progression and proliferation of ERalpha-positive breast cancer cells by supporting transcription of ERalpha and cyclin B1. (PMID:20103625)
• Data report the identification of the related proteins Sipl1 (Shank-interacting protein-like 1) and Rbck1 (RBCC protein interacting with PKC1) as novel interaction partners of Eya1. (PMID:20956555)
• analysis of recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex (PMID:22139374)
• The solution structure of the HOIL1 Ubl domain was solved using NMR spectroscopy to compare it with that of parkin to determine the structural elements responsible for S5a subunit of the 26S proteasome intermolecular interactions. (PMID:22517668)
• Estrogen receptor-alpha, RBCK1, and protein kinase C beta 1 cooperate to regulate estrogen receptor-alpha gene expression. (PMID:23042805)
• Patients from two kindreds of a new fatal inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis carried biallelic loss-of-expression and loss-of-function mutations in HOIL1. (PMID:23104095)
• Suggest that RBCK1 is important for the ubiquitination of PXR and may play a role in its proteasomal degradation. (PMID:23160820)
• RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy. (PMID:23798481)
• findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy. (PMID:23912458)
• 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)
• Late in the NF-kappaB activation cycle HOIL1 cleavage transiently reduces linear ubiquitination, including of NEMO and RIP1, dampening NF-kappaB activation and preventing reactivation. (PMID:26525107)
• results unveil HOIL1 as a negative regulator of lymphocyte activation cleaved by MALT1. (PMID:27006117)
• HOXA1-mediated activation of NF-kappaB is non-transcriptional and the RBCK1 and TRAF2 influences on NF-kappaB are epistatic to HOXA1 (PMID:27382069)
• LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation. (PMID:27810922)
• The binding of SHARPIN or HOIL-1L facilitates the E2 loading of HOIP. (PMID:28978479)
• This study demonstrated that Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction. (PMID:29260357)
• RBCK1 expression is upregulated in human renal cell carcinoma (RCC) samples. Analysis of multiple public databases revealed the correlation between RBCK1 expression and poor prognosis in RCC patients. RBCK1 depletion experiments in RCC cells severely affected the in vivo and in vitro proliferation of RCCs. The effects of RBCK1 on cell proliferation could be rescued with p53 expression knockdown. (PMID:30874541)
• RBCK1 modulated chemosensitivity in colorectal cancer. (PMID:31545242)
• HOIL-1, an atypical E3 ligase that controls MyD88 signalling by forming ester bonds between ubiquitin and components of the Myddosome. (PMID:31615747)
• Cross-regulation between LUBAC and caspase-1 modulates cell death and inflammation. (PMID:32122970)
• RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature. (PMID:32187699)
• Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders. (PMID:32403254)
• Regulation of PTEN and ovarian cancer progression by an E3 ubiquitin ligase RBCK1. (PMID:35174471)
• HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation. (PMID:35274759)
• RBCK1 is an endogenous inhibitor for triple negative breast cancer via hippo/YAP axis. (PMID:36280829)
• RBCK1 regulates the progression of ER-positive breast cancer through the HIF1alpha signaling. (PMID:36473847)
• RBCK1 Overexpression Attenuates Inflammation and Mobility of Derp1-Induced Nasal Mucosal Cells by Downregulating NLRP3. (PMID:36702106)
• Mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN. (PMID:37976837)
• RBCK1 overexpression is associated with immune cell infiltration and poor prognosis in hepatocellular carcinoma. (PMID:38214606)
• HOIL-1L deficiency induces cell cycle alteration which causes immaturity of skeletal muscle and cardiomyocytes. (PMID:38632277)
• E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation. (PMID:38763208)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbck1	ENSDARG00000031954
mus_musculus	Rbck1	ENSMUSG00000027466
rattus_norvegicus	Rbck1	ENSRNOG00000006695

Paralogs (2): RNF216 (ENSG00000011275), SHARPIN (ENSG00000179526)

Protein

Protein identifiers

RanBP-type and C3HC4-type zinc finger-containing protein 1 — Q9BYM8 (reviewed: Q9BYM8)

Alternative names: HBV-associated factor 4, Heme-oxidized IRP2 ubiquitin ligase 1, Hepatitis B virus X-associated protein 4, RING finger protein 54, RING-type E3 ubiquitin transferase HOIL-1, Ubiquitin-conjugating enzyme 7-interacting protein 3

All UniProt accessions (11): Q9BYM8, A0A8V8TLQ1, A0A8V8TMQ4, A0A8V8TMZ2, A6PVJ5, A6PVJ6, A6PVJ7, B4DML5, G3XAG9, H0Y4S7, Q5JWR1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates. Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination. Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. 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. 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. 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. Interacts with beta-I-type (PRKCB1) and zeta-type protein kinase C (PRKCZ). Interacts with UBE2L3. Interacts with PRKCH. Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner. Interacts with EYA1, TAB2, TAB3, MAP3K7 TRAF6 and RIPK1. Interacts with IRF3. Interacts with IREB2 only in iron-rich conditions. Interacts with IREB2 only in iron-rich conditions. (Microbial infection) Interacts with hepatitis B virus/HBV protein HBx; this interaction is required to activate transcription of the viral genome.

Post-translational modifications. Auto-ubiquitinated. Auto-ubiquitination leads to degradation by the proteasome. Phosphorylated. In vitro, phosphorylation inhibits auto-ubiquitination activity. (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. Polyglucosan body myopathy 1 with or without immunodeficiency (PGBM1) [MIM:615895] A disease characterized by polyglucosan storage myopathy associated with early-onset progressive muscle weakness and progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. Some patients present with severe immunodeficiency, invasive bacterial infections and chronic autoinflammation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RanBP2-type zinc finger, also called Npl4 zinc finger (NZF), mediates binding to ‘Met-1’-linked polyubiquitins. The UBL domain mediates association with RNF31 via interaction with its UBA domain.

Induction. By viral transfection.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the RBR family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BYM8-1	1, HOIL-1L	yes
Q9BYM8-3	2
Q9BYM8-4	3

RefSeq proteins (6): NP_001310885, NP_001310887, NP_001310889, NP_001397699, NP_006453, NP_112506* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR001841	Znf_RING	Domain
IPR001876	Znf_RanBP2	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR027370	Znf-RING_euk	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR044066	TRIAD_supradom	Domain
IPR047557	Rcat_RBR_HOIL1	Domain
IPR047558	BRcat_RBR_HOIL1	Domain
IPR047559	HOIL1_RBR_mRING-HC-C3HC3D	Domain
IPR051628	LUBAC_E3_Ligases	Family
IPR057468	HOIL-1/Sharpin_LTM	Domain

Pfam: PF13445, PF25393

UniProt features (84 total): binding site 20, strand 19, helix 11, turn 9, region of interest 5, zinc finger region 4, modified residue 3, splice variant 3, sequence variant 2, mutagenesis site 2, chain 1, domain 1, coiled-coil region 1, compositionally biased region 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8K6Q	X-RAY DIFFRACTION	1.59
9EGW	X-RAY DIFFRACTION	1.78
7YUJ	X-RAY DIFFRACTION	1.86
7V8E	X-RAY DIFFRACTION	1.9
9EGV	X-RAY DIFFRACTION	2
8BVL	X-RAY DIFFRACTION	2.24
7YUI	X-RAY DIFFRACTION	2.6
4DBG	X-RAY DIFFRACTION	2.71
8EAZ	X-RAY DIFFRACTION	3.08
2CRC	SOLUTION NMR
2LGY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYM8-F1	84.34	0.44

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 (1): 460

Ligand- & substrate-binding residues (20): 282; 285; 300; 302; 305; 308; 323; 332; 371; 376; 391; 394 …

Post-translational modifications (3): 1, 50, 330

Mutagenesis-validated functional residues (2):

Position	Phenotype
282	binds to ireb2 in iron-treated cells. reversed iron-induced down-regulation of ireb2. no ubiquitination of heme-loaded i
285	binds to ireb2 in iron-treated cells. reversed iron-induced down-regulation of ireb2. no ubiquitination of heme-loaded i

Function

Pathways and Gene Ontology

Reactome pathways

4 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-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 376 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, MODULE_151, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, CCATCCA_MIR432, PATIL_LIVER_CANCER, PUJANA_CHEK2_PCC_NETWORK, IRF7_01, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (19): protein polyubiquitination (GO:0000209), canonical NF-kappaB signal transduction (GO:0007249), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), 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), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), 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), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), positive regulation of metabolic process (GO:0009893), positive regulation of macromolecule metabolic process (GO:0010604), protein ubiquitination (GO:0016567), positive regulation of apoptotic process (GO:0043065), positive regulation of DNA-templated transcription (GO:0045893), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (11): transcription coactivator activity (GO:0003713), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), ubiquitin protein ligase activity (GO:0061630), protein sequestering activity (GO:0140311), ubiquitin ligase activator activity (GO:1990757), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): cytosol (GO:0005829), LUBAC complex (GO:0071797)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	3
Class I MHC mediated antigen processing & presentation	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
positive regulation of intracellular signal transduction	2
regulation of metabolic process	2
protein binding	2
protein ubiquitination	1
intracellular signaling cassette	1
defense response	1
response to bacterium	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	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
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
extrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
metabolic process	1
positive regulation of cellular process	1
positive regulation of metabolic process	1
macromolecule metabolic process	1
regulation of macromolecule metabolic process	1
protein modification by small protein conjugation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
primary metabolic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-like protein binding	1

Protein interactions and networks

STRING

1434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBCK1	RNF31	Q96EP0	998
RBCK1	SHARPIN	Q9H0F6	986
RBCK1	TRIM17	Q9Y577	959
RBCK1	IREB2	P48200	901
RBCK1	IKBKG	Q9Y6K9	812
RBCK1	A0A087WY85	A0A087WY85	775
RBCK1	BIRC2	Q13490	766
RBCK1	CYLD	Q9NQC7	766
RBCK1	PRKCH	P24723	748
RBCK1	RIPK1	Q13546	734
RBCK1	OTULIN	Q96BN8	724
RBCK1	TRIM37	O94972	707
RBCK1	TRADD	Q15628	706
RBCK1	TNFRSF1A	P19438	667
RBCK1	IKBKB	O14920	664

IntAct

244 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
TNF	TNFRSF1A	psi-mi:“MI:0914”(association)	0.960
SHARPIN	RNF31	psi-mi:“MI:0914”(association)	0.960

BioGRID (790): RBCK1 (Affinity Capture-Western), PRKCA (Biochemical Activity), RBCK1 (Two-hybrid), RBCK1 (Two-hybrid), RBCK1 (Two-hybrid), RBCK1 (Two-hybrid), NDUFAF3 (Two-hybrid), TSSK3 (Two-hybrid), SYCE1 (Two-hybrid), RBCK1 (Affinity Capture-Western), IKBKG (Biochemical Activity), UBC (Biochemical Activity), UBE2D3 (Reconstituted Complex), UBE2D1 (Reconstituted Complex), UBE2D2 (Reconstituted Complex)

ESM2 similar proteins: A4IIY1, A5PK27, E7FAM5, O94806, O94844, P21860, P42694, P50747, P97711, Q15139, Q1PSW8, Q2TBA3, Q2YDF9, Q496Y0, Q4KLT0, Q5BIM1, Q5RB22, Q5RFV4, Q5XIS9, Q60553, Q62101, Q62921, Q6DDJ3, Q6DFV5, Q6DH94, Q6DJB3, Q6DLV9, Q6NYU2, Q6PFY8, Q7T0P6, Q7Z419, Q80WC9, Q8BKD6, Q8BWW9, Q8BZ03, Q8HXH0, Q8K1Y2, Q8R023, Q91009, Q920N2

Diamond homologs: A9JTG5, E1BDF2, E6ZIJ1, Q62921, Q91WA6, Q9BYM8, Q9EQL9, Q9H0F6, Q9WUB0

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	RBCK1	ubiquitination
RBCK1	“form complex”	LUBAC	binding
RBCK1	“down-regulates quantity by destabilization”	IRF3	polyubiquitination
RBCK1	“down-regulates quantity by destabilization”	BACH1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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	10	62.2×	1e-13
TICAM1, RIP1-mediated IKK complex recruitment	5	55.6×	1e-06
TNF signaling	7	54.8×	4e-09
TNFR1-induced proapoptotic signaling	6	48.8×	1e-07
IKK complex recruitment mediated by RIP1	5	46.0×	3e-06
Regulation of TNFR1 signaling	10	41.5×	5e-12
NOD1/2 Signaling Pathway	7	41.1×	3e-08
TAK1-dependent IKK and NF-kappa-B activation	6	33.4×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	10	47.0×	2e-12
protein K63-linked ubiquitination	11	37.7×	2e-12
protein polyubiquitination	15	22.2×	1e-13
tumor necrosis factor-mediated signaling pathway	5	21.2×	2e-04
obsolete positive regulation of NF-kappaB transcription factor activity	7	18.4×	1e-05
negative regulation of canonical NF-kappaB signal transduction	7	15.4×	3e-05
protein autoubiquitination	5	15.0×	8e-04
positive regulation of canonical NF-kappaB signal transduction	14	13.0×	5e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	10
Uncertain significance	214
Likely benign	253
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070681	NM_031229.4(RBCK1):c.586_596del (p.Gly196fs)	Pathogenic
1072347	NM_031229.4(RBCK1):c.949C>T (p.Gln317Ter)	Pathogenic
1075761	NM_031229.4(RBCK1):c.663del (p.Glu222fs)	Pathogenic
1393408	NM_031229.4(RBCK1):c.751C>T (p.Gln251Ter)	Pathogenic
140623	NM_031229.4(RBCK1):c.553C>T (p.Gln185Ter)	Pathogenic
140624	NM_031229.4(RBCK1):c.121_122del (p.Leu41fs)	Pathogenic
140625	NM_031229.4(RBCK1):c.896_899del (p.Glu299fs)	Pathogenic
140627	NM_031229.4(RBCK1):c.727G>T (p.Glu243Ter)	Pathogenic
140628	NM_031229.4(RBCK1):c.724_727dup (p.Glu243fs)	Pathogenic
140629	NM_031229.4(RBCK1):c.790C>T (p.Gln264Ter)	Pathogenic
1686122	NM_031229.4(RBCK1):c.994_999del (p.Cys332_Ser333del)	Pathogenic
1693520	NM_031229.4(RBCK1):c.691del (p.Gln231fs)	Pathogenic
1693523	NM_031229.4(RBCK1):c.817dup (p.Leu273fs)	Pathogenic
1998491	NM_031229.4(RBCK1):c.772C>T (p.Gln258Ter)	Pathogenic
202236	GRCh37/hg19 20p13(chr20:71023-2129746)x1	Pathogenic
2029817	NM_031229.4(RBCK1):c.1111dup (p.Cys371fs)	Pathogenic
2105689	NM_031229.4(RBCK1):c.49C>T (p.Arg17Ter)	Pathogenic
2229016	NM_031229.4(RBCK1):c.748dup (p.Tyr250fs)	Pathogenic
2703812	NM_031229.4(RBCK1):c.701_708dup (p.Ala238fs)	Pathogenic
2706120	NM_031229.4(RBCK1):c.1386G>A (p.Trp462Ter)	Pathogenic
2738369	NM_031229.4(RBCK1):c.1136G>A (p.Trp379Ter)	Pathogenic
3248308	NC_000020.10:g.(?389402)(443049_?)del	Pathogenic
3248309	NC_000020.10:g.(?389402)(398594_?)del	Pathogenic
3248312	NC_000020.10:g.(?389402)(402902_?)del	Pathogenic
3649308	NM_031229.4(RBCK1):c.1154dup (p.Asp385fs)	Pathogenic
3724651	NM_031229.4(RBCK1):c.936_945del (p.Ile313fs)	Pathogenic
4713986	NM_031229.4(RBCK1):c.1143_1144dup (p.Phe382fs)	Pathogenic
4720630	NM_031229.4(RBCK1):c.716_717del (p.Arg239fs)	Pathogenic
4725106	NM_031229.4(RBCK1):c.176_177dup (p.Ser60Ter)	Pathogenic
4732433	NM_031229.4(RBCK1):c.1178dup (p.Cys394fs)	Pathogenic

SpliceAI

2979 predictions. Top by Δscore:

Variant	Effect	Δscore
20:417520:CTGCA:C	acceptor_loss	1.0000
20:417521:TGCA:T	acceptor_loss	1.0000
20:417522:GCA:G	acceptor_loss	1.0000
20:417523:CA:C	acceptor_loss	1.0000
20:417524:A:AG	acceptor_gain	1.0000
20:417524:AG:A	acceptor_gain	1.0000
20:417524:AGG:A	acceptor_loss	1.0000
20:417524:AGGCT:A	acceptor_gain	1.0000
20:417525:G:GA	acceptor_gain	1.0000
20:417525:GG:G	acceptor_gain	1.0000
20:417525:GGCT:G	acceptor_gain	1.0000
20:417525:GGCTG:G	acceptor_gain	1.0000
20:417620:G:GA	donor_loss	1.0000
20:417621:T:G	donor_loss	1.0000
20:417624:G:GG	donor_gain	1.0000
20:417727:ACCAG:A	acceptor_gain	1.0000
20:417730:A:AG	acceptor_gain	1.0000
20:417730:AG:A	acceptor_gain	1.0000
20:417731:G:GT	acceptor_gain	1.0000
20:417731:GG:G	acceptor_gain	1.0000
20:417731:GGT:G	acceptor_gain	1.0000
20:417731:GGTT:G	acceptor_gain	1.0000
20:417731:GGTTT:G	acceptor_gain	1.0000
20:417926:GGAAG:G	donor_gain	1.0000
20:417927:GAAG:G	donor_gain	1.0000
20:417927:GAAGG:G	donor_gain	1.0000
20:417928:A:T	donor_gain	1.0000
20:417928:AAGGT:A	donor_loss	1.0000
20:417931:G:GC	donor_loss	1.0000
20:417931:G:GG	donor_gain	1.0000

AlphaMissense

3331 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:427394:T:A	C371S	0.999
20:427394:T:C	C371R	0.999
20:427395:G:C	C371S	0.999
20:427396:C:G	C371W	0.999
20:427454:T:C	C391R	0.999
20:428981:T:C	C447R	0.999
20:429035:T:C	C465R	0.999
20:429059:T:C	C473R	0.999
20:417771:T:A	W101R	0.998
20:417771:T:C	W101R	0.998
20:419566:G:C	W197C	0.998
20:419566:G:T	W197C	0.998
20:422176:T:C	C323R	0.998
20:427395:G:A	C371Y	0.998
20:427409:T:C	C376R	0.998
20:427410:G:A	C376Y	0.998
20:427411:C:G	C376W	0.998
20:427478:T:C	C399R	0.998
20:427480:C:G	C399W	0.998
20:427487:T:A	C402S	0.998
20:427487:T:C	C402R	0.998
20:427488:G:C	C402S	0.998
20:428990:T:A	C450S	0.998
20:428990:T:C	C450R	0.998
20:428991:G:C	C450S	0.998
20:429035:T:A	C465S	0.998
20:429036:G:C	C465S	0.998
20:429037:C:G	C465W	0.998
20:429044:T:C	C468R	0.998
20:429060:G:A	C473Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000199903 (20:414535 C>A,T), RS1000269190 (20:419167 G>A,C), RS1000278703 (20:424890 C>T), RS1000308395 (20:421412 C>T), RS1000517448 (20:417907 A>AG), RS1000535374 (20:415957 C>T), RS1000697028 (20:411734 A>ACTT), RS1000716454 (20:419960 T>C), RS1000731772 (20:425719 C>T), RS1000787396 (20:419003 G>A), RS1000915921 (20:410306 G>A), RS1001003876 (20:420256 C>A,T), RS1001023502 (20:411565 C>T), RS1001087497 (20:416211 G>A), RS1001157122 (20:425725 C>G)

Disease associations

OMIM: gene MIM:610924 | disease phenotypes: MIM:615895, MIM:232500

GenCC curated gene-disease

Disease	Classification	Inheritance
polyglucosan body myopathy 1 with or without immunodeficiency	Strong	Autosomal recessive
autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis	Supportive	Autosomal recessive
polyglucosan body myopathy type 1	Supportive	Autosomal recessive

Mondo (4): polyglucosan body myopathy 1 with or without immunodeficiency (MONDO:0014389), glycogen storage disease due to glycogen branching enzyme deficiency (MONDO:0009292), autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis (MONDO:0017992), (MONDO:0018348)

Orphanet (3): Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis (Orphanet:329173), Polyglucosan body myopathy type 1 (Orphanet:397937), Glycogen storage disease due to glycogen branching enzyme deficiency (Orphanet:367)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000508	Ptosis
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis
HP:0001019	Erythroderma
HP:0001250	Seizure
HP:0001324	Muscle weakness
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001744	Splenomegaly
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002027	Abdominal pain
HP:0002028	Chronic diarrhea
HP:0002037	Inflammation of the large intestine
HP:0002240	Hepatomegaly
HP:0002573	Hematochezia
HP:0002650	Scoliosis
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002721	Immunodeficiency
HP:0002840	Lymphadenitis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003542_11	Night sleep phenotypes	8.000000e-08
GCST012490_144	Femur bone mineral density x serum urate levels interaction	4.000000e-08
GCST012490_453	Femur bone mineral density x serum urate levels interaction	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296109 (PROTEIN COMPLEX)

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 1 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

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	4
sodium arsenite	decreases expression, increases expression	3
Cisplatin	decreases expression, affects response to substance	2
Dexamethasone	decreases expression, affects cotreatment, increases expression	2
bisphenol F	affects cotreatment, increases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
3,4-dichloroaniline	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
nickel sulfate	decreases expression	1
hydroquinone	increases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, increases 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
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Ethanol	increases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	increases phosphorylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
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

1 cell lines: 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3KG	N/Tert-1 RBCK1	Telomerase immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00947960	PHASE2	COMPLETED	Triheptanoin Treatment Trial for Patients With Adult Polyglucosan Body Disease
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT02683512	Not specified	RECRUITING	GBE Deficiency (GSD IV and APBD) Natural History Study