SHARPIN

Summary

SHARPIN (SHANK associated RH domain interactor, HGNC:25321) is a protein-coding gene on chromosome 8q24.3, encoding Sharpin (Q9H0F6). Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation.

Enables polyubiquitin modification-dependent protein binding activity. Involved in defense response to bacterium; protein linear polyubiquitination; and regulation of signal transduction. Located in cytosol. Part of LUBAC complex.

Source: NCBI Gene 81858 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammation with episodic fever and immune dysregulation (Strong, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 90 total — 3 pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_030974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25321
Approved symbol	SHARPIN
Name	SHANK associated RH domain interactor
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434N1923, SIPL1
Ensembl gene	ENSG00000179526
Ensembl biotype	protein_coding
OMIM	611885
Entrez	81858

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 24 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000359551, ENST00000398712, ENST00000525275, ENST00000530216, ENST00000531375, ENST00000532536, ENST00000533184, ENST00000533948, ENST00000534242, ENST00000534435, ENST00000876467, ENST00000876468, ENST00000876469, ENST00000876470, ENST00000876471, ENST00000876472, ENST00000876473, ENST00000876474, ENST00000876475, ENST00000876476, ENST00000876477, ENST00000876478, ENST00000922422, ENST00000922423, ENST00000922424, ENST00000964195, ENST00000964196, ENST00000964197, ENST00000964198, ENST00000964199, ENST00000964200, ENST00000964201

RefSeq mRNA: 1 — MANE Select: NM_030974 NM_030974

CCDS: CCDS43777

Canonical transcript exons

ENST00000398712 — 9 exons

Exon	Start	End
ENSE00001419331	144098637	144098788
ENSE00001759060	144099277	144099430
ENSE00001779709	144099081	144099205
ENSE00002191595	144103553	144103773
ENSE00003491637	144099703	144099844
ENSE00003503632	144099510	144099618
ENSE00003534273	144103051	144103225
ENSE00003654199	144098866	144098994
ENSE00003668636	144099929	144100069

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.8760 / max 158.7819, expressed in 1817 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95615	17.5999	1811
95618	4.4281	1540
95619	3.4240	1580
95617	0.2922	147
95614	0.0767	13
95616	0.0436	8
95623	0.0114	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	99.11	gold quality
left testis	UBERON:0004533	99.09	gold quality
apex of heart	UBERON:0002098	97.19	gold quality
testis	UBERON:0000473	96.75	gold quality
mucosa of transverse colon	UBERON:0004991	96.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.00	gold quality
right adrenal gland	UBERON:0001233	95.99	gold quality
granulocyte	CL:0000094	95.95	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.92	gold quality
right adrenal gland cortex	UBERON:0035827	95.86	gold quality
lower esophagus mucosa	UBERON:0035834	95.82	gold quality
right uterine tube	UBERON:0001302	95.75	gold quality
body of stomach	UBERON:0001161	95.74	gold quality
lower esophagus	UBERON:0013473	95.66	gold quality
left adrenal gland cortex	UBERON:0035825	95.66	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.66	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.57	gold quality
left adrenal gland	UBERON:0001234	95.55	gold quality
right lobe of thyroid gland	UBERON:0001119	95.48	gold quality
metanephros cortex	UBERON:0010533	95.46	gold quality
left coronary artery	UBERON:0001626	95.34	gold quality
transverse colon	UBERON:0001157	95.29	gold quality
left uterine tube	UBERON:0001303	95.29	gold quality
right coronary artery	UBERON:0001625	95.19	gold quality
body of uterus	UBERON:0009853	95.18	gold quality
left lobe of thyroid gland	UBERON:0001120	95.04	gold quality
thoracic aorta	UBERON:0001515	95.04	gold quality
ascending aorta	UBERON:0001496	95.02	gold quality
endocervix	UBERON:0000458	95.00	gold quality
adrenal cortex	UBERON:0001235	94.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

6 targeting SHARPIN, 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-29B-2-5P	99.67	68.98	1726
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-4274	98.59	66.10	630
HSA-MIR-1182	96.41	64.89	336
HSA-MIR-193A-5P	95.70	65.33	613

Literature-anchored findings (GeneRIF, showing 39)

• Suggest that Sharpin is not an inert scaffold protein, but may play tumor-associated roles during cancer biogenesis. (PMID:20179993)
• 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)
• SHARPIN is an additional component of LUBAC; SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-kappaB (PMID:21455180)
• SHARPIN inhibits the critical switching of beta1-integrins from inactive to active conformations. (PMID:21947080)
• the crystal structure of the N-terminal portion of SHARPIN, which adopts the highly conserved pleckstrin homology superfold that is often used as a scaffold to create protein interaction modules (PMID:22549881)
• crystals of SHARPIN belonged to the primitive tetragonal space group P4(3)2(1)2, with unit-cell parameters a = b = 61.55, c = 222.81 A (PMID:22750873)
• SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells. (PMID:24210817)
• SIPL1 promotes AKT activation by decreasing the amount of PTEN protein in CHO-K1 cells. (PMID:25018115)
• SIPL1 binds PTEN and enhances PTEN polyubiquitination. (PMID:25152374)
• Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. (PMID:25443631)
• progesterone significantly reduced SIPL1 mRNA and protein expression in MCF7 cells. As progesterone enhances breast cancer tumorigenesis in context dependent manner, inhibition of SIPL1 expression may contribute to progesterone’s non-tumorigenic function (PMID:25992689)
• Data show that SHANK-associated RH domain interacting protein (SHARPIN) gene expression in breast cancer patients predicts clinical outcomes. (PMID:26506596)
• the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct. (PMID:26600301)
• LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation. (PMID:27810922)
• Our study firstly identifies the role of SHARPIN in promoting wild-type P53 degradation and correlates with poor prognosis in P53 wild-type breast cancer. (PMID:28063307)
• Overexpression of SHARPIN in Prostate cancer cells promoted cell growth and reduced apoptosis through NF-kB/ERK/Akt pathway and apoptosis-associated proteins. SHARPIN enhances the metastasis of prostate cancer and impair patient survivals. (PMID:28230260)
• the present study found that loss of the NEMO-SHARPIN interaction impaired recruitment of truncated NEMO forms into punctuate structures that are transiently formed on cell stimulation and thus led to a defect in linear ubiquitination (PMID:28249776)
• Sharpin-Arp2/3 interaction promotes lamellipodium formation. (PMID:28775156)
• The binding of SHARPIN or HOIL-1L facilitates the E2 loading of HOIP. (PMID:28978479)
• identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis. (PMID:29227283)
• SIPL1 contributes to promote resistance to tamoxifen in Breast cancer cells through both AKT and NF-kappaB actions. (PMID:29248549)
• Sharpin has a primary role during development of atopic dermatitis; it induces elevated expression of IL-33 and its orphan receptor ST2, FLG and STAT3 and NF-kappaB inactivation in HaCaT keratinocytes (PMID:30230040)
• SHARPIN functions in the human megakaryocyte/platelet lineage through protein interactions at the nexus of integrin and immune/inflammatory signaling. (PMID:30804189)
• SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway. (PMID:31401046)
• SHARPIN overexpression promotes TAK1 expression and activates JNKs and NF-kappaB pathway in Mycosis Fungoides. (PMID:31461795)
• SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling. (PMID:31884247)
• Cross-regulation between LUBAC and caspase-1 modulates cell death and inflammation. (PMID:32122970)
• SHARPIN regulates cell proliferation of cutaneous basal cell carcinoma via inactivation of the transcriptional factors GLI2 and cJUN. (PMID:32319607)
• Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders. (PMID:32403254)
• Imaging genomics discovery of a new risk variant for Alzheimer’s disease in the postsynaptic SHARPIN gene. (PMID:32558014)
• Downregulation of SHANK-associated RH domain-interacting protein elevates interleukin-33 expression by stimulating the Janus kinase 2/signal transducer and activator of transcription signalling pathway in HaCaT cells. (PMID:33548083)
• SHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel-Lindau protein ubiquitination and degradation. (PMID:34339558)
• A functional variant of SHARPIN confers increased risk of late-onset Alzheimer’s disease. (PMID:34737388)
• A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages. (PMID:34785643)
• Biochemical and functional characterization of the N-terminal ubiquitin-like domain of human SHARPIN. (PMID:34965468)
• SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling. (PMID:35968603)
• Mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN. (PMID:37976837)
• Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. (PMID:38609546)
• SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression. (PMID:39450547)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbck1	ENSDARG00000031954
danio_rerio	shrprbck1r	ENSDARG00000059871
danio_rerio	sharpin	ENSDARG00000076995
mus_musculus	Sharpin	ENSMUSG00000022552
rattus_norvegicus	Sharpin	ENSRNOG00000012812

Paralogs (2): RNF216 (ENSG00000011275), RBCK1 (ENSG00000125826)

Protein

Protein identifiers

Sharpin — Q9H0F6 (reviewed: Q9H0F6)

Alternative names: Shank-associated RH domain-interacting protein, Shank-interacting protein-like 1

All UniProt accessions (2): Q9H0F6, H0YCU2

UniProt curated annotations — full annotation on UniProt →

Function. Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner 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.

Subunit / interactions. Monomer and homodimer. 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 with EYA1, EYA2, SHANK1 and SHANK3 (via ANK repeats).

Subcellular location. Cytoplasm. Cytosol. Synapse.

Tissue specificity. Highly expressed in skeletal muscle and placenta and at lower levels in brain, heart, colon without mucosa, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes. Up-regulated in various tumor tissues such as kidney, liver, ovary and pancreas tumors.

Disease relevance. Autoinflammation with episodic fever and immune dysregulation (AIFID) [MIM:620795] An autosomal recessive disorder characterized by recurrent fever and autoinflammation with onset in infancy or early childhood. Variable clinical manifestations include lymphadenopathy, hepatosplenomegaly, gastrointestinal inflammation, polyarthritis and joint inflammation, parotitis, and immune dysregulation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Ubiquitin-like domain is required for the interaction with RNF31. The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. Binds preferentially linear polyubiquitin chains and ‘Lys-63’-linked polyubiquitin chains over ‘Lys-48’-linked polyubiquitin chains. Also binds monoubiquitin.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H0F6-1	1	yes
Q9H0F6-2	2, hSIPL1A

RefSeq proteins (1): NP_112236* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001876	Znf_RanBP2	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR031912	Sharpin_PH	Domain
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR051628	LUBAC_E3_Ligases	Family
IPR057468	HOIL-1/Sharpin_LTM	Domain

Pfam: PF16764, PF25393

UniProt features (46 total): strand 12, mutagenesis site 7, helix 7, region of interest 4, sequence variant 3, sequence conflict 3, modified residue 2, splice variant 2, compositionally biased region 2, chain 1, domain 1, zinc finger region 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8K6P	X-RAY DIFFRACTION	1.86
4EMO	X-RAY DIFFRACTION	2
5X0W	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0F6-F1	75.78	0.47

Functional residue map

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

Post-translational modifications (2): 312, 165

Mutagenesis-validated functional residues (7):

Position	Phenotype
114	abolishes homodimerization.
272	abolishes interaction with rnf31 and ability to mediate linear polyubiquitination.
354	abolishes binding to ubiquitin without affecting interaction with rnf31; when associated with s-357.
357	abolishes binding to ubiquitin without affecting interaction with rnf31; when associated with s-354.
358–359	abolishes binding to ubiquitin and ability to mediate linear polyubiquitination.
368	abolishes binding to ubiquitin without affecting interaction with rnf31; when associated with s-371.
371	abolishes binding to ubiquitin without affecting interaction with rnf31; when associated with s-368.

Function

Pathways and Gene Ontology

Reactome pathways

9 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-6794361	Neurexins and neuroligins
R-HSA-112316	Neuronal System
R-HSA-162582	Signal Transduction
R-HSA-6794362	Protein-protein interactions at synapses
R-HSA-73887	Death Receptor Signaling
R-HSA-75893	TNF signaling

MSigDB gene sets: 229 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, PATIL_LIVER_CANCER, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, GOBP_EPIDERMIS_DEVELOPMENT

GO Biological Process (14): mitochondrion organization (GO:0007005), canonical NF-kappaB signal transduction (GO:0007249), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), apoptotic nuclear changes (GO:0030262), keratinization (GO:0031424), 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), negative regulation of inflammatory response (GO:0050728), protein linear polyubiquitination (GO:0097039), regulation of CD40 signaling pathway (GO:2000348), epidermis development (GO:0008544), protein ubiquitination (GO:0016567)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), protein-macromolecule adaptor activity (GO:0030674), polyubiquitin modification-dependent protein binding (GO:0031593), ubiquitin binding (GO:0043130), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): cytosol (GO:0005829), synapse (GO:0045202), LUBAC complex (GO:0071797), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
TNF signaling	3
Protein-protein interactions at synapses	1
Neuronal System	1
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
cellular anatomical structure	2
organelle organization	1
intracellular signaling cassette	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cellular component disassembly involved in execution phase of apoptosis	1
keratinocyte differentiation	1
multicellular organismal process	1
defense response	1
response to bacterium	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
protein polyubiquitination	1
regulation of signal transduction	1
CD40 signaling pathway	1
tissue development	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein binding	1
molecular adaptor activity	1
modification-dependent protein binding	1
ubiquitin-like protein binding	1
binding	1
cation binding	1
cytoplasm	1
cell junction	1
ubiquitin ligase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1562 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHARPIN	RNF31	Q96EP0	998
SHARPIN	RBCK1	Q9BYM8	986
SHARPIN	RIPK1	Q13546	818
SHARPIN	OTULIN	Q96BN8	810
SHARPIN	SHANK2	Q9UPX8	805
SHARPIN	BIRC2	Q13490	801
SHARPIN	CYLD	Q9NQC7	765
SHARPIN	IREB2	P48200	763
SHARPIN	TRADD	Q15628	737
SHARPIN	TRIP6	Q15654	696
SHARPIN	CHUK	O15111	675
SHARPIN	PTEN	P60484	667
SHARPIN	FADD	Q13158	654
SHARPIN	KIT	P10721	640
SHARPIN	TRAF6	Q9Y4K3	620

IntAct

132 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
RBCK1	RNF31	psi-mi:“MI:0915”(physical association)	0.980
RNF31	SHARPIN	psi-mi:“MI:0915”(physical association)	0.960
SHARPIN	RNF31	psi-mi:“MI:0914”(association)	0.960
SHARPIN	RNF31	psi-mi:“MI:0407”(direct interaction)	0.960

BioGRID (342): SHARPIN (Affinity Capture-Western), ITGAL (Reconstituted Complex), ITGAL (Far Western), SHARPIN (Protein-peptide), SHARPIN (Protein-peptide), SHARPIN (Protein-peptide), SHARPIN (Affinity Capture-Western), PTEN (Affinity Capture-Western), IKBKG (Affinity Capture-Western), CHUK (Affinity Capture-Western), IKBKB (Affinity Capture-Western), SHARPIN (Affinity Capture-Western), SHARPIN (Reconstituted Complex), SHARPIN (Affinity Capture-MS), SHARPIN (Affinity Capture-MS)

ESM2 similar proteins: A1L515, A4D2P6, A6QQD2, A8VU90, E1BDF2, O75808, O88995, P0CG25, P22083, Q0IIA6, Q2TA57, Q3B7L1, Q3MIP1, Q3U5Q7, Q3UR50, Q3UR97, Q3UV16, Q400G9, Q5BKX5, Q5EBM0, Q5GH72, Q5SZI1, Q5TM19, Q5U4P2, Q62994, Q659K9, Q6PRD1, Q7Z736, Q861W0, Q86UR1, Q8BNN1, Q8C0R7, Q8CG70, Q8IUW3, Q8IVL6, Q8N398, Q8NAG6, Q8NCW0, Q8R2H1, Q8VCE9

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

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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	13	89.1×	1e-20
TNFR1-induced proapoptotic signaling	9	80.7×	9e-14
TICAM1, RIP1-mediated IKK complex recruitment	6	73.6×	8e-09
TNF signaling	8	69.1×	1e-11
IKK complex recruitment mediated by RIP1	6	60.8×	3e-08
Regulation of TNFR1 signaling	12	54.8×	3e-16
NOD1/2 Signaling Pathway	8	51.8×	1e-10
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	5	36.4×	7e-06

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of necroptotic process	5	90.1×	3e-07
canonical NF-kappaB signal transduction	12	79.9×	6e-18
tumor necrosis factor-mediated signaling pathway	7	42.0×	5e-08
positive regulation of extrinsic apoptotic signaling pathway	5	41.4×	9e-06
obsolete positive regulation of NF-kappaB transcription factor activity	9	33.6×	1e-09
negative regulation of canonical NF-kappaB signal transduction	10	31.3×	2e-10
positive regulation of canonical NF-kappaB signal transduction	20	26.4×	7e-21
positive regulation of non-canonical NF-kappaB signal transduction	5	23.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	58
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3233309	NM_030974.4(SHARPIN):c.220dup (p.Leu74fs)	Pathogenic
3233310	NM_030974.4(SHARPIN):c.613_614del (p.Leu205fs)	Pathogenic
4818857	NM_030974.4(SHARPIN):c.738_739del (p.His247fs)	Pathogenic

SpliceAI

2462 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144098990:CTGGG:C	acceptor_gain	1.0000
8:144098995:C:CC	acceptor_gain	1.0000
8:144099272:CTGA:C	donor_loss	1.0000
8:144099273:TGAC:T	donor_loss	1.0000
8:144099274:GACCT:G	donor_loss	1.0000
8:144099275:A:C	donor_loss	1.0000
8:144099276:C:CG	donor_loss	1.0000
8:144099428:CAC:C	acceptor_gain	1.0000
8:144099430:CCTG:C	acceptor_loss	1.0000
8:144099431:CTGTG:C	acceptor_loss	1.0000
8:144099697:CCTCA:C	donor_loss	1.0000
8:144099698:CTCA:C	donor_loss	1.0000
8:144099699:TCACC:T	donor_loss	1.0000
8:144099700:CA:C	donor_loss	1.0000
8:144099730:T:TA	donor_gain	1.0000
8:144099840:CTCTT:C	acceptor_gain	1.0000
8:144099841:TCTT:T	acceptor_loss	1.0000
8:144099842:CTT:C	acceptor_gain	1.0000
8:144099843:TT:T	acceptor_gain	1.0000
8:144099845:C:CC	acceptor_gain	1.0000
8:144099845:CT:C	acceptor_loss	1.0000
8:144099846:T:A	acceptor_loss	1.0000
8:144099848:CAGGG:C	acceptor_gain	1.0000
8:144099849:A:T	acceptor_gain	1.0000
8:144099852:G:C	acceptor_gain	1.0000
8:144099852:G:GC	acceptor_gain	1.0000
8:144103104:T:TA	donor_gain	1.0000
8:144105631:A:AG	acceptor_gain	1.0000
8:144105635:CCCA:C	acceptor_loss	1.0000
8:144105637:CA:C	acceptor_loss	1.0000

AlphaMissense

2435 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144099391:A:G	W270R	0.996
8:144099391:A:T	W270R	0.996
8:144099389:C:A	W270C	0.994
8:144099389:C:G	W270C	0.994
8:144099411:A:G	F263S	0.991
8:144099395:T:A	Q268H	0.988
8:144099395:T:G	Q268H	0.988
8:144099390:C:G	W270S	0.986
8:144098939:C:G	C368S	0.983
8:144098940:A:T	C368S	0.983
8:144098965:G:C	F359L	0.981
8:144098965:G:T	F359L	0.981
8:144098967:A:G	F359L	0.981
8:144099351:A:T	L283H	0.981
8:144098982:A:G	C354R	0.978
8:144098986:C:A	W352C	0.977
8:144098986:C:G	W352C	0.977
8:144103213:A:G	W72R	0.977
8:144103213:A:T	W72R	0.977
8:144098940:A:G	C368R	0.975
8:144099307:A:C	Y298D	0.975
8:144099520:A:T	L253H	0.975
8:144098939:C:T	C368Y	0.972
8:144099303:A:G	L299S	0.972
8:144098930:C:G	C371S	0.971
8:144098931:A:T	C371S	0.971
8:144099309:A:T	L297H	0.970
8:144099315:G:T	A295D	0.970
8:144098959:A:C	N361K	0.969
8:144098959:A:T	N361K	0.969

dbSNP variants (sampled 300 via entrez): RS1000048438 (8:144104070 G>A,T), RS1000142958 (8:144104206 C>T), RS1000907203 (8:144102100 G>A), RS1001144884 (8:144103415 T>C), RS1001513053 (8:144100435 G>C), RS1001681091 (8:144102563 C>G), RS1001774318 (8:144102872 TAGG>T), RS1001808550 (8:144104989 G>T), RS1002644366 (8:144105493 G>A,T), RS1002682204 (8:144101174 A>G), RS1002780727 (8:144101533 C>A,T), RS1003212463 (8:144101365 T>C), RS1003252858 (8:144104932 G>C,T), RS1003592275 (8:144101665 A>C,G), RS1003690936 (8:144100041 C>A,G)

Disease associations

OMIM: gene MIM:611885 | disease phenotypes: MIM:620795

GenCC curated gene-disease

Disease	Classification	Inheritance
autoinflammation with episodic fever and immune dysregulation	Strong	Autosomal recessive

Mondo (2): autoinflammation with episodic fever and immune dysregulation (MONDO:0968982), Sharpin-related autoinflammatory syndrome (MONDO:1040029)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000389	Chronic otitis media
HP:0001369	Arthritis
HP:0001744	Splenomegaly
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002240	Hepatomegaly
HP:0002573	Hematochezia
HP:0002583	Colitis
HP:0002716	Lymphadenopathy
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003593	Infantile onset
HP:0006568	Increased hepatic glycogen content
HP:0011463	Childhood onset
HP:0011850	Parotitis
HP:0030057	Autoimmune antibody positivity
HP:0410295	Complete or near-complete absence of specific antibody response to tetanus vaccine

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004600_47	Eosinophil percentage of white cells	6.000000e-16
GCST004606_163	Eosinophil count	9.000000e-16
GCST004617_163	Eosinophil percentage of granulocytes	5.000000e-16
GCST004623_119	Neutrophil percentage of granulocytes	2.000000e-15
GCST004624_122	Sum eosinophil basophil counts	6.000000e-15
GCST006249_14	Serum metabolite levels	8.000000e-51
GCST009798_65	Asthma	1.000000e-08
GCST010043_161	Asthma	6.000000e-10
GCST90002381_464	Eosinophil count	9.000000e-32
GCST90002382_263	Eosinophil percentage of white cells	5.000000e-37

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count

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

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	affects phosphorylation	1
moringin	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pinostrobin	increases expression	1
jinfukang	increases expression	1
MT19c compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cannabidiol	decreases expression	1
Doxorubicin	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
Vanadates	increases expression	1
Antirheumatic Agents	increases expression	1
Acrylamide	decreases expression	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

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TK98	HAP1 SHARPIN (-) 1	Cancer cell line	Male
CVCL_XS77	HAP1 SHARPIN (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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