CALCOCO2

Summary

CALCOCO2 (calcium binding and coiled-coil domain 2, HGNC:29912) is a protein-coding gene on chromosome 17q21.32, encoding Calcium-binding and coiled-coil domain-containing protein 2 (Q13137). Xenophagy-specific receptor required for autophagy-mediated intracellular bacteria degradation.

This gene encodes a coiled-coil domain-containing protein. The encoded protein functions as a receptor for ubiquitin-coated bacteria and plays an important role in innate immunity by mediating macroautophagy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 10241 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 65 total
• GTEx eGene: eQTL in 39 tissues, sQTL in 49 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.93 (unconstrained)
• MANE Select transcript: NM_005831
• Interaction hub: 1,866 STRING partners (top 9% of genes corpus-wide)
• Notable: 65 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29912
Approved symbol	CALCOCO2
Name	calcium binding and coiled-coil domain 2
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	MGC17318, NDP52
Ensembl gene	ENSG00000136436
Ensembl biotype	protein_coding
OMIM	604587
Entrez	10241

Gene structure

Transcript identifiers

Ensembl transcripts: 60 — 33 protein_coding, 13 nonsense_mediated_decay, 11 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000258947

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 11, TSL 3: 6, TSL 4: 4, TSL 5: 4

ENST00000258947, ENST00000372317, ENST00000416445, ENST00000448105, ENST00000502761, ENST00000503463, ENST00000505071, ENST00000506971, ENST00000507076, ENST00000507306, ENST00000508679, ENST00000509014, ENST00000509112, ENST00000509415, ENST00000509507, ENST00000509784, ENST00000510356, ENST00000510997, ENST00000511697, ENST00000511816, ENST00000513119, ENST00000514006, ENST00000514267, ENST00000514962, ENST00000570513, ENST00000575461, ENST00000575560, ENST00000576582, ENST00000866560, ENST00000866561, ENST00000866562, ENST00000866563, ENST00000866564, ENST00000866565, ENST00000866566, ENST00000945215, ENST00000945216, ENST00000945217, ENST00000945218, ENST00000945219, ENST00000945220, ENST00000945221, ENST00000945222, ENST00000945223, ENST00000977847, ENST00001027825, ENST00001027826, ENST00001027827, ENST00001027828, ENST00001027829, ENST00001027831, ENST00001027832, ENST00001027833, ENST00001027834, ENST00001027835, ENST00001027838, ENST00001116584, ENST00001126835, ENST00001126836, ENST00001137508

RefSeq mRNA: 5 — MANE Select: NM_005831 NM_001261390, NM_001261391, NM_001261393, NM_001261395, NM_005831

CCDS: CCDS11538, CCDS58558, CCDS58559, CCDS58560, CCDS58561

Canonical transcript exons

ENST00000258947 — 13 exons

Exon	Start	End
ENSE00000736220	48848322	48848455
ENSE00001193163	48862838	48865245
ENSE00002031081	48831035	48831078
ENSE00003469848	48849252	48849377
ENSE00003502827	48848064	48848166
ENSE00003509420	48856092	48856187
ENSE00003519816	48851089	48851177
ENSE00003520930	48852926	48853012
ENSE00003527764	48860314	48860449
ENSE00003533873	48851559	48851628
ENSE00003551196	48852506	48852628
ENSE00003563449	48862276	48862304
ENSE00003669218	48841698	48841887

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 85.4956 / max 2004.3277, expressed in 1826 samples.

Highest expression (Bgee): calcaneal tendon, mucosa of stomach, lung, colonic epithelium, sural nerve.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CALCOCO2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 39 tissues and its splicing (sQTL) in 49 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 88 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	sqtl	3.6e-229	+1.76	17:48849253:G:A
Artery Tibial	sqtl	5.3e-204	+1.72	17:48849253:G:A
Muscle Skeletal	sqtl	5.3e-202	+1.66	17:48849253:G:A
Esophagus Muscularis	sqtl	5.0e-165	+1.86	17:48849253:G:A
Cells Cultured fibroblasts	sqtl	1.1e-153	+1.63	17:48849253:G:A
Lung	sqtl	4.5e-149	+1.72	17:48849253:G:A
Breast Mammary Tissue	sqtl	7.8e-138	+1.70	17:48849253:G:A
Skin Sun Exposed Lower leg	sqtl	9.2e-127	-1.66	17:48849253:G:A
Testis	sqtl	1.9e-118	+1.85	17:48849253:G:A
Artery Aorta	sqtl	7.7e-113	+1.80	17:48849253:G:A
Thyroid	sqtl	9.4e-106	-1.64	17:48849253:G:A
Heart Atrial Appendage	sqtl	1.7e-98	+1.76	17:48849253:G:A
Skin Not Sun Exposed Suprapubic	sqtl	3.0e-96	-1.68	17:48849253:G:A
Whole Blood	sqtl	3.3e-92	-1.51	17:48849253:G:A
Esophagus Mucosa	sqtl	3.5e-92	-1.69	17:48849253:G:A
Cells EBV-transformed lymphocytes	sqtl	9.0e-91	+1.72	17:48849253:G:A
Esophagus Gastroesophageal Junction	sqtl	2.0e-89	+1.65	17:48849253:G:A
Colon Transverse	sqtl	1.3e-86	-1.85	17:48849253:G:A
Colon Sigmoid	sqtl	4.6e-66	-1.73	17:48849253:G:A
Heart Left Ventricle	sqtl	5.1e-64	+1.64	17:48849253:G:A

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
161463	83.4679	1826
161468	0.7986	306
161466	0.7081	226
161467	0.3089	131
161465	0.1628	87
161464	0.0494	20

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.04	gold quality
mucosa of stomach	UBERON:0001199	98.95	gold quality
right lung	UBERON:0002167	98.89	gold quality
colonic epithelium	UBERON:0000397	98.85	gold quality
sural nerve	UBERON:0015488	98.76	gold quality
left testis	UBERON:0004533	98.43	gold quality
tibial nerve	UBERON:0001323	98.32	gold quality
right testis	UBERON:0004534	98.29	gold quality
rectum	UBERON:0001052	98.16	gold quality
popliteal artery	UBERON:0002250	98.13	gold quality
tibial artery	UBERON:0007610	98.12	gold quality
monocyte	CL:0000576	98.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.10	gold quality
lower esophagus	UBERON:0013473	98.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.08	gold quality
artery	UBERON:0001637	98.04	gold quality
mononuclear cell	CL:0000842	98.02	gold quality
left coronary artery	UBERON:0001626	97.99	gold quality
right atrium auricular region	UBERON:0006631	97.98	gold quality
leukocyte	CL:0000738	97.96	gold quality
descending thoracic aorta	UBERON:0002345	97.96	gold quality
omental fat pad	UBERON:0010414	97.94	gold quality
ectocervix	UBERON:0012249	97.94	gold quality
heart left ventricle	UBERON:0002084	97.93	gold quality
peritoneum	UBERON:0002358	97.93	gold quality
apex of heart	UBERON:0002098	97.89	gold quality
cardiac ventricle	UBERON:0002082	97.87	gold quality
aorta	UBERON:0000947	97.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.83	gold quality
endocervix	UBERON:0000458	97.79	gold quality
coronary artery	UBERON:0001621	97.72	gold quality
islet of Langerhans	UBERON:0000006	97.71	gold quality
gastrocnemius	UBERON:0001388	97.69	gold quality
left ovary	UBERON:0002119	97.65	gold quality
right coronary artery	UBERON:0001625	97.63	gold quality
transverse colon	UBERON:0001157	97.62	gold quality
muscle of leg	UBERON:0001383	97.62	gold quality
heart	UBERON:0000948	97.61	gold quality
upper lobe of left lung	UBERON:0008952	97.61	gold quality
left uterine tube	UBERON:0001303	97.56	gold quality
thoracic aorta	UBERON:0001515	97.54	gold quality
cardiac atrium	UBERON:0002081	97.53	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.51	gold quality
ascending aorta	UBERON:0001496	97.48	gold quality
body of uterus	UBERON:0009853	97.48	gold quality
upper lobe of lung	UBERON:0008948	97.45	gold quality
gall bladder	UBERON:0002110	97.44	gold quality
esophagus	UBERON:0001043	97.38	gold quality
left lobe of thyroid gland	UBERON:0001120	97.31	gold quality
adipose tissue	UBERON:0001013	97.27	gold quality
right ovary	UBERON:0002118	97.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.21	gold quality
colon	UBERON:0001155	97.19	gold quality
skin of leg	UBERON:0001511	97.19	gold quality
large intestine	UBERON:0000059	97.16	gold quality
intestine	UBERON:0000160	97.14	gold quality
right lobe of thyroid gland	UBERON:0001119	97.13	gold quality
connective tissue	UBERON:0002384	97.10	gold quality
small intestine	UBERON:0002108	97.07	gold quality
thyroid gland	UBERON:0002046	97.06	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.03	gold quality
skin of abdomen	UBERON:0001416	96.98	gold quality
sigmoid colon	UBERON:0001159	96.97	gold quality
stromal cell of endometrium	CL:0002255	96.96	gold quality
body of stomach	UBERON:0001161	96.96	gold quality
heart right ventricle	UBERON:0002080	96.91	gold quality
vagina	UBERON:0000996	96.90	gold quality
stomach	UBERON:0000945	96.72	gold quality
pancreas	UBERON:0001264	96.70	gold quality
esophagus mucosa	UBERON:0002469	96.69	gold quality
uterine cervix	UBERON:0000002	96.60	gold quality
fundus of stomach	UBERON:0001160	96.60	gold quality
urinary bladder	UBERON:0001255	96.60	gold quality
body of pancreas	UBERON:0001150	96.59	gold quality
mucosa of transverse colon	UBERON:0004991	96.59	gold quality
right adrenal gland cortex	UBERON:0035827	96.58	gold quality
granulocyte	CL:0000094	96.57	gold quality
minor salivary gland	UBERON:0001830	96.54	gold quality
metanephros cortex	UBERON:0010533	96.51	gold quality
zone of skin	UBERON:0000014	96.50	gold quality
muscle organ	UBERON:0001630	96.49	gold quality
skeletal muscle organ	UBERON:0014892	96.49	gold quality
left adrenal gland	UBERON:0001234	96.46	gold quality
right adrenal gland	UBERON:0001233	96.36	gold quality
testis	UBERON:0000473	96.31	gold quality
adenohypophysis	UBERON:0002196	96.29	gold quality
adrenal gland	UBERON:0002369	96.29	gold quality
left adrenal gland cortex	UBERON:0035825	96.25	gold quality
palpebral conjunctiva	UBERON:0001812	96.17	gold quality
mouth mucosa	UBERON:0003729	96.15	gold quality
lung	UBERON:0002048	96.13	gold quality
adrenal cortex	UBERON:0001235	96.05	gold quality
eye	UBERON:0000970	96.04	gold quality
ovary	UBERON:0000992	96.04	gold quality
vermiform appendix	UBERON:0001154	96.01	gold quality
saliva-secreting gland	UBERON:0001044	95.92	gold quality
spleen	UBERON:0002106	95.92	gold quality
caecum	UBERON:0001153	95.87	gold quality
tonsil	UBERON:0002372	95.86	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	432.20
E-MTAB-7303	no	122.39
E-MTAB-6678	no	3.49
E-CURD-112	no	2.70
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	159.1
Choroid plexus	tissue	130.9
Testis	tissue	127.2	low
Skeletal muscle	tissue	122.2	low
Spinal cord	tissue	121.7
Liver	tissue	112.3	low
Adipose tissue	tissue	110.6	low
Heart muscle	tissue	102.2	low
Corpus callosum	tissue	97.8
Rectum	tissue	95.1	medium
Colon	tissue	94.6	medium
Medulla oblongata	tissue	88.2
Midbrain	tissue	83.6
Substantia nigra	tissue	83.4
Esophagus	tissue	83.2	low
Ovary	tissue	83.0	low
Smooth muscle	tissue	81.9	low
Lung	tissue	76.3	medium
Superior colliculi	tissue	75.9
Thalamus	tissue	75.4
Cervix	tissue	74.4	low
Parathyroid gland	tissue	72.0	low
Pons	tissue	71.3
Small intestine	tissue	71.0	medium
Vagina	tissue	70.9	not detected
Periaqueductal gray	tissue	70.9
Retina	tissue	70.8
Thyroid gland	tissue	70.5	medium
Kidney	tissue	70.5	medium
Thymus	tissue	69.3
Seminal vesicle	tissue	68.2	low
Spleen	tissue	64.7	not detected
Duodenum	tissue	64.1	medium
Breast	tissue	63.3	low
Tonsil	tissue	62.8	medium
Gallbladder	tissue	62.1	medium
Urinary bladder	tissue	61.6	medium
Hypothalamus	tissue	61.5
Fallopian tube	tissue	60.8	medium
Placenta	tissue	59.4	medium
Bone marrow	tissue	59.3	medium
Stomach 1	tissue	58.2	medium
Epididymis	tissue	57.6	medium
Endometrium 1	tissue	55.3	low
Adrenal gland	tissue	54.2	low
Locus coeruleus	tissue	53.7
Septum	tissue	53.5
Pancreas	tissue	53.3	medium
Skin 1	tissue	53.0	low
Hippocampal formation	tissue	52.9
Putamen	tissue	52.3
Prostate	tissue	52.1	low
Appendix	tissue	52.1	medium
Lymph node	tissue	49.7	low
Salivary gland	tissue	49.5	low
Ventral forebrain	tissue	48.0
Cerebral cortex	tissue	47.5	medium
Motor cortex	tissue	47.5
Olfactory bulb	tissue	46.8
Hippocampus	tissue	46.4	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Blood vessel (122.9), Ventral spinal cord (121.7), Dorsal spinal cord (118.1), White matter (97.8), Cerebellar white matter (84.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CALCOCO2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 84 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-12124	99.68	69.17	2700

Functional genomics

gnomAD constraint: pLI 0.000196, LOEUF 0.933, missense Z 1.06 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000258947 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:48,841,708–48,848,075	48 / 79.3	0.61	no
17:48,848,076–48,852,599	236 / 225.3	1.05	no
17:48,852,600–48,863,002	172 / 210.3	0.82	no

Literature-anchored findings (GeneRIF, showing 40)

• interacts with ICP4 regulatory protein of HSV-1 during early stage of infection (PMID:14747555)
• NDP52 was identified as a myosin VI binding protein; results suggest that myosin VI-T6BP-NDP52 complexes may play a role in coordinating cytokine signalling and membrane transport pathways with actin filament organisation and cell adhesion (PMID:17635994)
• NDP52 recognizes ubiquitin-coated Salmonella enterica and recruits TBK1. (PMID:19820708)
• p62 and NDP52 act cooperatively to drive efficient antibacterial autophagy by targeting the protein complexes they coordinate to distinct microdomains associated with bacteria (PMID:21079414)
• ND10 and ND10 components might be important defensive factors against the CMV cross-species infection (PMID:21552525)
• p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. (PMID:21646350)
• a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF-TRAF6. (PMID:21964925)
• Data show that the selectivity of the autophagy receptor NDP52 for LC3C is crucial for innate immunity since cells lacking either protein cannot protect their (PMID:23022382)
• Data show that the miRNA-processing enzyme, DICER and the main miRNA effector, AGO2, are targeted for degradation as miRNA-free entities (PMID:23143396)
• Autophagy of Tax1bp1/Ndp52 promotes non-canonical NF-kappaB signalling. (PMID:23209807)
• Data indicate that the binding site in galectin-8 is essential for the recruitment of the autophagy receptor NDP52 to cytosol-exposed Salmonella Typhimurium. (PMID:23386746)
• Dimeric NDP52 forms a ternary complex with two monomeric galectin-8 molecules as well as two LC3C molecules (PMID:23511477)
• The missense SNP rs2303015 (Val248Ala) in the NDP52 was associated with Crohn’s disease. (PMID:23624108)
• the role of ORF75 in the antagonization of ND10-mediated intrinsic immunity (PMID:24453968)
• data support a model in which non-ND10 resident Sp100 acts as a negative regulator of polycomb repressive complex-2 (PRC2) recruitment, and suggest that KSHV may actively escape ND10 silencing mechanisms to promote establishment of latent chromatin. (PMID:25033267)
• control retrotransposon insertion in the genome (PMID:25366815)
• These data show that NDP52 promotes the maturation of autophagosomes via its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct LC3-interacting region, and with MYOSIN VI. (PMID:25771791)
• two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy (PMID:26266977)
• Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis. (PMID:26493630)
• insight into how CALCOCO2 targets ubiquitin-decorated pathogens for autophagic degradations (PMID:26506893)
• The authors identify calcium-binding and coiled-coil domain 2 (CALCOCO2, also known as NDP52) as a binding partner of influenza A virus PB1-F2. (PMID:28613140)
• The authors propose that Rab35-GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52. (PMID:28848034)
• findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. (PMID:28965816)
• Backfolding of MVI regulates its ability to bind DNA and that a putative transcription co-activator NDP52 relieves the auto-inhibition of MVI to enable DNA binding. Additionally, we show that the MVI-NDP52 complex binds RNAPII, which is critical for transcription, and that depletion of NDP52 or MVI reduces steady-state mRNA levels. (PMID:29187741)
• Studies suggest that the nature of the regulatory mechanism(s) that governs nuclear dot protein 52 (NDP52) engagement during autophagosome maturation remains to be determined [Review]. (PMID:29395717)
• The CALCOCO2, but not SQSTM1, suppresses the antiviral type I interferon signaling by promoting autophagy-mediated degradation of the mitochondrial antiviral signaling (MAVS) protein. (PMID:30154446)
• These results indicate that NDP52 and MTPAP form an autophagy receptor complex, which enhances autophagic elimination of damaged mitochondria. (PMID:30309841)
• evaluated the currently known TBK1-mediated phosphorylation sites in the SKICH domains of NDP52 and TAX1BP1 on the basis of their interactions with NAP1 (PMID:30459273)
• The capability of NDP52 to induce mitophagy is dependent on its interaction with the FIP200/ULK1 complex, which is facilitated by TBK1. Ectopically tethering ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. (PMID:30853401)
• we show that, essential for anti-bacterial autophagy, the cargo receptor NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1, which are subunits of the autophagy-initiating ULK and the TBK1 kinase complex, respectively. FIP200 and SINTBAD/NAP1 are each recruited independently to bacteria via NDP52, as revealed by selective point mutations in their respective binding sites (PMID:30853402)
• The altered expression of NRBP2 and CALCOCO2 is associated with left ventricular dysfunction parameters in human dilated cardiomyopathy. (PMID:31009519)
• The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. (PMID:32773036)
• Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy. (PMID:33723372)
• Crosstalk Between NDP52 and LUBAC in Innate Immune Responses, Cell Death, and Xenophagy. (PMID:33815386)
• Baicalein Activates Parkin-Dependent Mitophagy through NDP52 and OPTN. (PMID:35406696)
• NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy. (PMID:36514953)
• Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells. (PMID:37777549)
• NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling. (PMID:37942585)
• CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway. (PMID:38752371)
• Vangl2 suppresses NF-kappaB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation. (PMID:39269442)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	calcoco2	ENSDARG00000052515
mus_musculus	Calcoco2	ENSMUSG00000006056
rattus_norvegicus	Calcoco2	ENSRNOG00000091290

Paralogs (2): CALCOCO1 (ENSG00000012822), TAX1BP1 (ENSG00000106052)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1343177) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal pelvic girdle bone morphology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R4U3	95.9%	Diamond
Bos taurus	Q2KJE0	92.4%	Diamond
Xenopus laevis	Q6DD09	83.9%	Diamond
Macaca fascicularis	Q4R914	80.5%	Diamond
Xenopus tropicalis	Q6P3P1	59.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TTLL6	protein-coding	284076
ATP5MC1	protein-coding	516
SNF8	protein-coding	11267
UBE2Z	protein-coding	65264

Protein

Protein identifiers

Calcium-binding and coiled-coil domain-containing protein 2 — Q13137 (reviewed: Q13137)

Alternative names: Antigen nuclear dot 52 kDa protein, Nuclear domain 10 protein NDP52, Nuclear dot protein 52

All UniProt accessions (10): D6RBF9, D6RBI4, D6REB0, D6RF70, D6RJE7, Q13137, H0Y9G3, H0YBP4, I3L493, I3L4E1

UniProt curated annotations — full annotation on UniProt →

Function. Xenophagy-specific receptor required for autophagy-mediated intracellular bacteria degradation. Acts as an effector protein of galectin-sensed membrane damage that restricts the proliferation of infecting pathogens such as Salmonella typhimurium upon entry into the cytosol by targeting LGALS8-associated bacteria for autophagy. Initially orchestrates bacteria targeting to autophagosomes and subsequently ensures pathogen degradation by regulating pathogen-containing autophagosome maturation. Bacteria targeting to autophagosomes relies on its interaction with MAP1LC3A, MAP1LC3B and/or GABARAPL2, whereas regulation of pathogen-containing autophagosome maturation requires the interaction with MAP3LC3C. May play a role in ruffle formation and actin cytoskeleton organization and seems to negatively regulate constitutive secretion.

Subunit / interactions. Dimer. Part of a complex consisting of CALCOCO2, TAX1BP1 and MYO6. Interacts with MYO6. Interacts with GEMIN4. Interacts with ATG8 family members MAP1LC3A, MAP1LC3B, GABARAP, GABARAPL1 and GABARAPL2. Interacts with ATG8 family member MAP1LC3C. Interacts with LGALS8. Interacts with TOM1; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and CALCOCO2. Interacts with AZI2. (Microbial infection) Interacts with Lassa virus protein Z. (Microbial infection) Interacts with Mopeia virus protein Z.

Subcellular location. Cytoplasm. Perinuclear region. Cytoskeleton. Cytoplasmic vesicle. Autophagosome membrane.

Tissue specificity. Expressed in all tissues tested with highest expression in skeletal muscle and lowest in brain.

Post-translational modifications. (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation. Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication.

Domain organisation. The MYO6-binding domain is required for autophagy-mediated degradation of infecting bacteria such as Salmonella typhimurium, but not for bacteria targeting to autophagosomes. The CLIR (LC3C-interacting region) motif is required for interaction with MAP1LC3C, but dispensable for CALCOCO2-mediated autophagosome maturation. The LIR-like motif is required for interaction with MAP1LC3A, MAP1LC3B and GABARAPL2, as well as for CALCOCO2-mediated autophagosome maturation. The LGALS8-binding domain is essential for the recruitment to cytosol-exposed infecting bacteria.

Induction. Treatment with IFNB1/IFN-beta and IFNG/IFN-gamma show an increase in number and size of CALCOCO2-specific dots and partial redistribution to the cytoplasm. IFNG/IFN-gamma increases gene expression only slightly and IFNB does not increase expression.

Similarity. Belongs to the CALCOCO family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q13137-1	1	yes
Q13137-2	2
Q13137-3	3
Q13137-4	4
Q13137-5	5

RefSeq proteins (5): NP_001248319, NP_001248320, NP_001248322, NP_001248324, NP_005822* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR041611	SKICH	Domain
IPR041641	CALCOCO1/2_Zn_UBZ1	Domain
IPR051002	UBA_autophagy_assoc_protein	Family

Pfam: PF17751

UniProt features (62 total): strand 15, helix 12, mutagenesis site 8, sequence variant 5, binding site 4, splice variant 4, region of interest 3, sequence conflict 2, turn 2, short sequence motif 2, chain 1, zinc finger region 1, modified residue 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures by resolution:

PDB	Title	Method	Resolution (Å)
3VVV	Skich domain of NDP52	X-RAY DIFFRACTION	1.35
5Z7L	Crystal structure of NDP52 SKICH region in complex with NAP1	X-RAY DIFFRACTION	2.02
4GXL	The crystal structure of Galectin-8 C-CRD in complex with NDP52	X-RAY DIFFRACTION	2.02
4XKL	Crystal structure of NDP52 ZF2 in complex with mono-ubiquitin	X-RAY DIFFRACTION	2.1
5Z7A	Crystal structure of NDP52 SKICH region	X-RAY DIFFRACTION	2.38
3VVW	NDP52 in complex with LC3C	X-RAY DIFFRACTION	2.5
4HAN	Crystal structure of Galectin 8 with NDP52 peptide	X-RAY DIFFRACTION	2.55
7EAA	crystal structure of NDP52 SKICH domain in complex with RB1CC1 coiled-coil domain	X-RAY DIFFRACTION	2.6
2MXP	Solution structure of NDP52 ubiquitin-binding zinc finger	SOLUTION NMR
5AAQ	TBK1 recruitment to cytosol-invading Salmonella induces anti- bacterial autophagy	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13137-F1	81.16	0.56

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; vesicles

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

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

Ligand- & substrate-binding residues (4)

Position	Role
425	Zn(2+)
440	Zn(2+)
444	Zn(2+)
422	Zn(2+)

Post-translational modifications (1)

Type	Positions
Phosphoserine	445

Mutagenesis-validated functional residues (8)

Position	Phenotype
136	abrogates the interaction with map1lc3c.
203–206	abrogates interaction with maplc3a, maplc3b and gabarapl2.
374	severely reduces affinity for lgals8.
376	severely reduces affinity for lgals8.
378	prevents interaction with lgals8.
380	severely reduced affinity for lgals8.
400	does not affect interaction with myo6.
425	fails interact with myo6 and to promote maturation of autophagosomes.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 141 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, GOBP_XENOPHAGY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_MACROAUTOPHAGY, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MARTINEZ_RB1_TARGETS_DN, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_TYPE_II_INTERFERON, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY

GO Biological Process (5): viral process (GO:0016032), response to type II interferon (GO:0034341), xenophagy (GO:0098792), positive regulation of autophagosome maturation (GO:1901098), autophagy (GO:0006914)

GO Molecular Function (4): zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (10): autophagosome membrane (GO:0000421), nucleus (GO:0005634), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), cytoskeleton (GO:0005856), membrane (GO:0016020), PML body (GO:0016605), cytoplasmic vesicle (GO:0031410), perinuclear region of cytoplasm (GO:0048471)

GO top-level categories

28 GO namespaces:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
biological_process	1
response to cytokine	1
innate immune response	1
macroautophagy	1
defense response to other organism	1
positive regulation of organelle organization	1
positive regulation of macroautophagy	1
positive regulation of protein-containing complex disassembly	1
autophagosome maturation	1
regulation of autophagosome maturation	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
cation binding	1
vacuolar membrane	1
autophagosome	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
vacuole	1
intracellular membraneless organelle	1
nuclear body	1
intracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
positive regulation of autophagosome maturation	BP	mutant phenotype
response to type II interferon	BP	direct assay
xenophagy	BP	mutant phenotype
PML body	CC	direct assay
autophagosome	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
membrane	CC	high-throughput assay
perinuclear region of cytoplasm	CC	direct assay
protein homodimerization activity	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,866 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALCOCO2	NBR1	Q14596	886
CALCOCO2	OPTN	Q96CV9	881
CALCOCO2	CD300C	Q08708	792
CALCOCO2	SQSTM1	Q13501	787
CALCOCO2	REXO4	Q9GZR2	758
CALCOCO2	ISG20	Q96AZ6	756
CALCOCO2	SP100	P23497	754
CALCOCO2	PINK1	Q9BXM7	751
CALCOCO2	GABARAPL2	P60520	740
CALCOCO2	F5GZY7	F5GZY7	738
CALCOCO2	BNIP3L	O60238	732
CALCOCO2	GATD3	P0DPI2	729
CALCOCO2	FUNDC1	Q8IVP5	719
CALCOCO2	LGALS8	O00214	719
CALCOCO2	BCL2L13	Q9BXK5	719

IntAct

Human interaction partners of CALCOCO2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 192 partners by confidence:

Partner	Interaction type	MIscore	Records
TCL1A	physical association	0.900	10
LGALS8	physical association	0.890	9
TBK1	physical association	0.840	3
METTL17	physical association	0.780	10
MOS	physical association	0.780	8
FAM90A1	physical association	0.780	7
FARS2	physical association	0.780	7
GABARAPL1	physical association	0.780	7
GABARAPL2	physical association	0.780	7
LSM4	physical association	0.780	7
NAA10	physical association	0.780	7
DUSP12	physical association	0.740	5
KANSL1	physical association	0.740	5
SRI	physical association	0.740	5
TP53RK	physical association	0.740	5
MXI1	physical association	0.720	9
LITAF	physical association	0.720	7
CBX8	physical association	0.720	6
DDX6	physical association	0.720	6
FAM161A	physical association	0.720	6
MAGOHB	physical association	0.720	6
PRPF31	physical association	0.720	6
RTP5	physical association	0.720	6
AMMECR1	physical association	0.670	7
ARHGEF39	physical association	0.670	5
TEKT3	physical association	0.670	5
DAZAP2	physical association	0.670	4
ENKD1	physical association	0.670	4
FBXL18	physical association	0.670	4
FNDC11	physical association	0.670	4

BioGRID (749 interactions; top human partners by supporting records in a sample of 600 records): UBC (Two-hybrid; 11 records), LGALS8 (Two-hybrid; 9 records), RB1CC1 (Reconstituted Complex; 8 records), AZI2 (Affinity Capture-MS; 7 records), GABARAPL2 (Two-hybrid; 6 records), MTPAP (Affinity Capture-MS; 6 records), RAB35 (Affinity Capture-Western; 6 records), TCL1A (Two-hybrid; 5 records), GABARAPL1 (Two-hybrid; 4 records), MAP1LC3A (Affinity Capture-Western; 4 records), MAP1LC3C (Two-hybrid; 4 records), MAVS (Affinity Capture-Western; 4 records), TBK1 (Affinity Capture-MS; 4 records), TBKBP1 (Affinity Capture-MS; 4 records), CDK7 (Affinity Capture-MS; 3 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
TBK1	“up-regulates activity”	CALCOCO2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 192 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
Regulation of NF-kappa B signaling	6	36.6×	7e-06
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	5	36.6×	2e-05
Translesion synthesis by POLI	5	32.3×	3e-05
TICAM1, RIP1-mediated IKK complex recruitment	5	28.9×	4e-05
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	5	28.9×	4e-05
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	5	25.0×	7e-05
activated TAK1 mediates p38 MAPK activation	5	23.9×	7e-05
IKK complex recruitment mediated by RIP1	5	23.9×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
type I interferon-mediated signaling pathway	6	12.7×	6e-03

Disease & clinical

Genetic variants

Variant evidence for CALCOCO2: 65 ClinVar records (0 pathogenic / likely pathogenic); 8 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	4
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 1,034):

Position(s)	Effect	Δscore	Sites
17:48848320–48848321	acceptor_loss	1.0000	5
17:48848456–48848457	donor_loss	1.0000	5
17:48849250–48849251	acceptor_loss	1.0000	5
17:48849378–48849379	donor_loss	1.0000	4
17:48851088	acceptor_loss	1.0000	2
17:48851178–48851179	donor_loss	1.0000	5
17:48851629–48851630	donor_loss	1.0000	4
17:48852504–48852505	acceptor_loss	1.0000	6
17:48852561	donor_gain	1.0000
17:48852594	donor_gain	1.0000

AlphaMissense

452 missense substitutions predicted likely pathogenic (of 3,007 scored), across 133 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F123	8	0.972	0.996
F25	8	0.959	0.991
D54	8	0.953	0.975
F93	8	0.950	0.996
F59	8	0.936	0.995
F107	8	0.915	0.996
F125	8	0.912	0.995
S120	8	0.902	0.997
H440	8	0.894	0.958
H444	8	0.881	0.960
D439	8	0.814	0.925
W55	7	0.973	0.984
W63	7	0.963	0.992
F72	7	0.962	0.996
W74	7	0.949	0.982
C40	7	0.915	0.984
C422	7	0.912	0.964
C108	7	0.909	0.980
C425	7	0.907	0.944
F437	7	0.805	0.931

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.23e-07

Disease associations

OMIM: gene MIM:604587 | disease phenotypes:

GWAS associations

8 associations:

Study	Trait	p-value
GCST90013406_220	Liver enzyme levels (alkaline phosphatase)	2e-14
GCST90011900_99	Serum alkaline phosphatase levels	3e-11
GCST90000025_680	Appendicular lean mass	2e-10
GCST006585_145	Blood protein levels	1e-8
GCST007576_153	Chronotype	2e-8
GCST005414_22	Type 2 diabetes	3e-8
GCST007517_23	Type 2 diabetes	3e-8
GCST007518_29	Type 2 diabetes (adjusted for BMI)	3e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004980	appendicular lean mass
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066361 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.18	Kd	666.9	nM	CHEMBL3752910
6.17	ED50	675.5	nM	CHEMBL3752910

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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149837: Binding affinity to human CALCOCO2 incubated for 45 mins by Kinobead based pull down assay	kd	0.6669	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
trichostatin A	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
tanshinone	increases expression	1
manganese chloride	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Gallic Acid	increases expression	1
Lead	decreases expression	1
Manganese	increases expression	1
Oxygen	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Urethane	increases expression	1
Cyclosporine	increases 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
CHEMBL5652879	Binding	Binding affinity to human CALCOCO2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Cellosaurus cell lines

9 cell lines: 9 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C2VN	HeLa S3 penta KO	Cancer cell line	Female
CVCL_C2VP	HeLa S3 penta KO-ATG13 KO	Cancer cell line	Female
CVCL_C2VQ	HeLa S3 penta KO-ATG14 KO	Cancer cell line	Female
CVCL_C2VR	HeLa S3 penta KO-TBK1 KO	Cancer cell line	Female
CVCL_C2VS	HeLa S3 penta KO-ULK1/ULK2 DKO	Cancer cell line	Female
CVCL_C2VT	HeLa S3 penta KO-TBK1/ULK1/ULK2 TKO	Cancer cell line	Female
CVCL_C8QB	HeLa S3 penta KO-AZI2/TBKBP1 DKO clone 20	Cancer cell line	Female
CVCL_C9DW	HeLa S3 penta KO-ULK1/ULK2 DKO-AZI2/TBKBP1 DKO	Cancer cell line	Female
CVCL_D2Q1	HeLa S3 penta KO-AZI2/TBKBP1 DKO clone 26	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CALCOCO2 across ~30M SureChEMBL compounds — explore on Sugi Predict.