CCL3L1

Summary

CCL3L1 (C-C motif chemokine ligand 3 like 1, HGNC:10628) is a protein-coding gene on chromosome 17q12 alternate reference locus, encoding C-C motif chemokine 3-like 1 (P16619). Chemotactic for lymphocytes and monocytes.

This gene is one of several cytokine genes that are clustered on the q-arm of chromosome 17. Cytokines are a family of secreted proteins that function in inflammatory and immunoregulatory processes. The protein encoded by this gene binds to several chemokine receptors, including chemokine binding protein 2 and chemokine (C-C motif) receptor 5 (CCR5). CCR5 is a co-receptor for HIV, and binding of this protein to CCR5 inhibits HIV entry. The copy number of this gene varies among individuals, where most individuals have one to six copies, and a minority of individuals have zero or more than six copies. There are conflicting reports about copy number variation of this gene and its correlation to disease susceptibility. This record represents one of two copies that are present on the ALT_REF_LOCI_2 alternate haplotype of the GRCh38 human reference genome assembly. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 6349 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 10 total — 1 pathogenic
• MANE Select transcript: NM_021006

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10628
Approved symbol	CCL3L1
Name	C-C motif chemokine ligand 3 like 1
Location	17q12 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	G0S19-2, LD78BETA
Ensembl gene	ENSG00000277768
OMIM	601395
Entrez	6349

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 1 — MANE Select: NM_021006 NM_021006

Canonical transcript exons

ENST00000615140 — 0 exons

Expression profiles

FANTOM5 (CAGE): breadth broad, TPM avg 278.9117 / max 22217.4925, expressed in 583 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165437	278.9117	583
208148	189.9090	467

Top tissues by expression

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

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	32595.70
E-MTAB-9435	yes	17223.79
E-GEOD-84465	yes	16820.28
E-MTAB-7407	yes	2848.56
E-CURD-46	yes	2302.47
E-CURD-55	yes	1517.97
E-MTAB-8894	yes	553.83
E-HCAD-4	yes	298.97
E-MTAB-6701	yes	75.32
E-HCAD-10	yes	15.32
E-MTAB-9467	no	5032.12
E-GEOD-139324	no	4914.33
E-GEOD-110499	no	2953.90
E-GEOD-124472	no	101.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC2, FOXL2, TBX21

Literature-anchored findings (GeneRIF, showing 40)

• Pro-2, Asp-6, Pro-8, and Thr-9 are critical for LD78beta binding to CCR5 and HIV-1 replication inhibition, and LD78beta binding to CCR5 is sufficient for the initial signal transduction of LD78beta (PMID:11734558)
• multiple copies of CCL3L1 and CCL4L1 present in a single diploid genome are the result of segmental duplication at chromosome 17q12 (PMID:15028295)
• significant interindividual & interpopulation differences in copy number of a segmental duplication encompassing the gene encoding CCL3L1; possession of CCL3L1 copy number lower than the population average associated with enhanced HIV/AIDS susceptibility (PMID:15637236)
• severe periodontal tissue destruction in Papillon-Lefevre syndrome may be related to excess accumulation of LD78beta and LD78alpha and dysregulation of the microbial-induced inflammatory response in the periodontium (PMID:15728180)
• Variations occur in systemic vasculitis and Kawasaki disease susceptibility. (PMID:15962231)
• confirms a crucial protective role of CCL3L1 from both HIV infection and disease progression, highlighting a previously not described functional up-regulation of this chemokine variant in both HIV-positive and -negative persons infected with HTLV-2 (PMID:17062725)
• Neither CCL3L1 nor CCL4L1 gene copy number variation showed appreciable impact on susceptibility to or control of HIV-1 infection. (PMID:17330138)
• Increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. CCR532 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1. (PMID:17604289)
• variation in the CCL3L1 copy number is apparently not a factor that determines the prognosis of chronic HIV-1 infection, even though it is linked to HIV-1 susceptibility (PMID:17874089)
• haplotypes HHE and HHG*2 influence the risk of SLE. The copy number of CCL3L1 influences risk of SLE and modifies the SLE-influencing effects associated with CCR5 genotypes. Findings implicate a key role of the CCL3L1-CCR5 axis in the pathogenesis of SLE. (PMID:17971457)
• women who had CD4 and CD8 Gag-specific responses had significantly lower viral loads (P=0.004) and higher CCL3L1 copy number (P=0.015) than those women with only CD8 Gag-specific responses. (PMID:18360285)
• the CCL3L1-CCR5 genotype has a role in progression to AIDS from HIV-1 infections (PMID:18776933)
• CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection (PMID:18989363)
• in addition to CCL3L copy number, certain genetic variants of one gene or both CCL3L1 and CCL3 may be influencing CCL3 production. (PMID:19055602)
• findings show that the CCL3L1/bcl-2-regulated anti-apoptotic pathway significantly contributes to reduction of HIV-1/gp120-induced neuronal apoptosis (PMID:19100722)
• The association between gene dosage in the gene encoding FCGR3B with the risk of developing autoimmune diseases and whether the observed associations are modified by the gene dosage in CCL3L1 are reported. (PMID:19741716)
• Findings do not support a relationship between the population-specific CCL3L1 gene copy number and HIV/AIDS susceptibility. (PMID:19812560)
• No substantial effect of CCL3L1 copy number variation on HIV-1 infection, viral load, or disease progression is reported. (PMID:19812561)
• There is an absence of any substantial effect of CCL3L1 copy number variation on HIV-1 infection, viral load or disease progression. (PMID:19812562)
• The experimental aspects of copy number variant assays at CCL3L1 using pcr are validated. (PMID:19812563)
• The CCR5-59029 AG genotype and CCL3L1 gene dose appeared to have synergistic or interactive effects and are expected to be involved in the host innate resistance to HIV-1 infection. (PMID:19886839)
• higher level of expression at systemic level is associated with protection from HIV-1 infection in women from Benin (PMID:19898927)
• Lower CCL3L1 gene copy number compared to the population median is associated with chronic hepatitis C. Copy number variation of host genes represents a novel class of genetic diversity associated with viral hepatitis. (PMID:20044164)
• A high CCL3L1 copy number (>2) was associated with an 80% reduced risk of acquiring HIV infection. (PMID:20095832)
• Although CCL3L1 copy number is enriched in uninfected Caucasians, in HIV-1-infected individuals CCL3L1 copy number did not correlate either with long-term nonprogression or with CD4 cell count or viral load in chronic progressors. (PMID:20442635)
• The CCL3L1-CCR5 axis may play an important role in Kawasaki Disease pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG. (PMID:20628649)
• Studies indicate that complete phenotypic impact requires dissecting the combinatorial genomic complexity posed by various proportions of distinct CCL3L and CCL4L genes among individuals. (PMID:20659124)
• CCL3L1 copy number variation has a role in susceptibility to HIV-1 infection (PMID:21209899)
• The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. (PMID:21592988)
• Copy number of CCL3L1 may influence asthma risk by modulating IL-10 expression (PMID:21816135)
• liver transplant recipients with high copy number of CCL3L1 gene had a significant higher risk of acute rejection (PMID:21919959)
• The number of CCL3L1 gene copies does not have a role in susceptibility to KD or CALs nor with IVIG resistance in Korean KD patients. (PMID:22450355)
• The data show no statistically significant association of MIP-1alpha protein levels with copy number. However, there was a significant correlation between copy number and CCL3L1:CCL3 mRNA ratio. (PMID:22476153)
• Examined a Zimbabwean study population for an association of CCL3L CNV with HIV status, progression and survival. Found no association between four CCL3L CNV strata and HIV status , CD4 T-cell count, viral load , or CCL3 protein levels. (PMID:22484760)
• Studied the copy number variation of the chemokine gene CCL3L1 with susceptibility to malaria. We identified a high level of copy number haplotype diversity and find some evidence for an association of low CCL3L1 copy number with protection from anaemia. (PMID:22484763)
• The results do not support involvement of the CCL3L1 copy number variants in rheumatoid arthritis susceptibility. (PMID:22785612)
• Studies indicate beta-defensins (DEFB4, DEFB103, DEFB104), chemokine ligand 3 like 1 (CCL3L1), Fc gamma receptor 3B (FCGR3B), and complement component C4 (C4) for copy number variation in disease association. (PMID:22837109)
• Studied copy number variation of the CCL3L1 gene in contributing to the host variation in susceptibility and response to HIV infection by analyzing a sub-Saharan African cohort. (PMID:24219137)
• no evidence for an influence of variation in genes coding for MIP-1alpha or CCR5 individually or together in susceptibility to clinically active TB (PMID:24405814)
• Characterization of CCL3L1 CNVs with droplet digital PCR methodology highlighted specific CN genotypes in a French family sample. A copy number polymorphism of a rheumatoid arthritis (RA) candidate gene was quantified, and its significant association with RA was revealed in a Tunisian sample. (PMID:26728148)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

C-C motif chemokine 3-like 1 — P16619 (reviewed: P16619)

Alternative names: G0/G1 switch regulatory protein 19-2, LD78-beta(1-70), PAT 464.2, Small-inducible cytokine A3-like 1, Tonsillar lymphocyte LD78 beta protein

All UniProt accessions (1): P16619

UniProt curated annotations — full annotation on UniProt →

Function. Chemotactic for lymphocytes and monocytes. Is a ligand for CCR1, CCR3 and CCR5. Is an inhibitor of HIV-1-infection. The processed form LD78-beta(3-70) shows a 20-fold to 30-fold higher chemotactic activity and is a very potent inhibitor of HIV-1-infection. LD78-beta(3-70) is also a ligand for CCR1, CCR3 and CCR5.

Subcellular location. Secreted.

Post-translational modifications. The N-terminal processed forms LD78-beta(3-70) and LD78-beta(5-70) are produced by proteolytic cleavage after secretion from peripheral blood monocytes. The cleavage to yield LD78-beta(3-70) is probably achieved by DPP4.

Polymorphism. The copy number of the CCL3L1 gene varies among individuals; most individuals have 1-6 copies in the diploid genome, although rare individuals have zero or more than 6 copies.

Similarity. Belongs to the intercrine beta (chemokine CC) family.

RefSeq proteins (1): NP_066286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000827	Chemokine_CC_CS	Conserved_site
IPR001811	Chemokine_IL8-like_dom	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (8 total): chain 3, disulfide bond 2, signal peptide 1, site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16619-F1	90.15	0.67

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): 25–26 (cleavage; by dpp4)

Disulfide bonds (2): 34–58, 35–74

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-6783783	Interleukin-10 signaling

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): inflammatory response (GO:0006954), negative regulation of cell population proliferation (GO:0008285), positive regulation of cell migration (GO:0030335), cell chemotaxis (GO:0060326), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), chemokine-mediated signaling pathway (GO:0070098), chemotaxis (GO:0006935), immune response (GO:0006955)

GO Molecular Function (4): chemokine activity (GO:0008009), CCR chemokine receptor binding (GO:0048020), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	2
chemokine receptor binding	2
defense response	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regulation of cell migration	1
positive regulation of cell motility	1
chemotaxis	1
cellular response to chemical stimulus	1
antimicrobial humoral response	1
G protein-coupled receptor signaling pathway	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
response to chemical	1
taxis	1
immune system process	1
response to stimulus	1
cytokine activity	1
cell chemotaxis	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCL3L1	CCR5	P51681	998
CCL3L1	CCR1	P32246	975
CCL3L1	CCR3	P51677	971
CCL3L1	CCR2	P41597	804
CCL3L1	ACKR2	O00590	774
CCL3L1	CXCL8	P10145	706
CCL3L1	CCL5	P13501	694
CCL3L1	IL1B	P01584	668
CCL3L1	TNF	P01375	668
CCL3L1	CX3CR1	P49238	643
CCL3L1	CCL20	P78556	638
CCL3L1	CCR7	P32248	629
CCL3L1	CXCL1	P09341	622
CCL3L1	CXCL10	P02778	617
CCL3L1	CD4	P01730	614

IntAct

14 interactions, top by confidence:

A	B	Type	Score
CCL3L1	SLC41A3	psi-mi:“MI:0915”(physical association)	0.560
CCL3L1	SGTB	psi-mi:“MI:0915”(physical association)	0.560
CCL3L1	MGST2	psi-mi:“MI:0915”(physical association)	0.560
CCL3L1	TMEM179B	psi-mi:“MI:0915”(physical association)	0.560
CCL3L1	QSOX1	psi-mi:“MI:0914”(association)	0.350
CCL3L1	SLC41A3	psi-mi:“MI:0915”(physical association)	0.000
CCL3L1	SGTB	psi-mi:“MI:0915”(physical association)	0.000
CCL3L1	TMEM179B	psi-mi:“MI:0915”(physical association)	0.000
CCL3L1	MGST2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (40): CCL3L3 (Two-hybrid), CCL3L3 (Two-hybrid), CCL3L3 (Two-hybrid), CCL3L3 (Two-hybrid), CCR5 (Reconstituted Complex), CTSV (Affinity Capture-MS), COL18A1 (Affinity Capture-MS), IDE (Affinity Capture-MS), ARSB (Affinity Capture-MS), PCOLCE2 (Affinity Capture-MS), H6PD (Affinity Capture-MS), SEMA3C (Affinity Capture-MS), TLN2 (Affinity Capture-MS), ADAMTS1 (Affinity Capture-MS), SULF2 (Affinity Capture-MS)

ESM2 similar proteins: A9QWQ1, O14625, O46675, O46676, O46677, O46678, O89098, O97919, P08317, P09340, P09341, P10147, P10855, P10889, P12850, P13236, P13501, P14095, P14097, P16619, P19875, P19876, P30782, P30882, P42831, P46632, P47854, P50229, P50230, P50231, P97272, Q17QA1, Q5EBF6, Q5I1Z0, Q5RA36, Q68A92, Q68AZ0, Q711P4, Q8HYQ1, Q8HYQ2

Diamond homologs: F5HET8, O00175, O00585, O00626, O55145, O88430, O97919, P10147, P10148, P10855, P13236, P13500, P13501, P14097, P14844, P16619, P27784, P28291, P28292, P30882, P42831, P46632, P47993, P49873, P50229, P50230, P50231, P51670, P51671, P52203, P55773, P55774, P61274, P61275, P78423, P80075, P80098, P80343, P82943, P97272

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
209211	NC_000017.10:g.(34360227_34437475)_(36214026_36473024)del	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

Disease associations

OMIM: gene MIM:601395 | disease phenotypes: MIM:614527

GenCC curated gene-disease

Mondo (1): chromosome 17q12 deletion syndrome (MONDO:0013797)

Orphanet (1): 17q12 microdeletion syndrome (Orphanet:261265)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005951_15	Body mass index	3.000000e-13
GCST006585_2559	Blood protein levels	2.000000e-34

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
nickel sulfate	increases expression	3
TL8-506	affects cotreatment, increases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases expression, affects cotreatment	1
bathocuproine sulfonate	decreases reaction, increases expression, affects cotreatment	1
4-phenylenediamine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Pioglitazone	decreases expression	1
Doxorubicin	increases expression	1
Eugenol	increases expression	1
Methotrexate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Poly I-C	affects cotreatment, increases expression	1
Selenium	increases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases expression	1
Dronabinol	increases expression	1
Zinc	decreases expression	1
Ionomycin	affects cotreatment, decreases reaction, increases expression	1
Aflatoxin B1	decreases methylation	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight