Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNLPK2C)

• DOT Name: C-type lectin domain family 4 member A (CLEC4A)
• Synonyms: C-type lectin DDB27; C-type lectin superfamily member 6; Dendritic cell immunoreceptor; Lectin-like immunoreceptor; CD antigen CD367
• Gene Name: CLEC4A
• Related Disease:
  Crohn disease
  Ulcerative colitis
  Allergy
  Autoimmune disease
  Systemic lupus erythematosus
• UniProt ID: CLC4A_HUMAN
• PDB ID: 5B1W; 5B1X
• Pfam ID: PF00059
• Sequence:
  MTSEITYAEVRFKNEFKSSGINTASSAASKERTAPHKSNTGFPKLLCASLLIFFLLLAIS
  FFIAFVIFFQKYSQLLEKKTTKELVHTTLECVKKNMPVEETAWSCCPKNWKSFSSNCYFI
  STESASWQDSEKDCARMEAHLLVINTQEEQDFIFQNLQEESAYFVGLSDPEGQRHWQWVD
  QTPYNESSTFWHPREPSDPNERCVVLNFRKSPKRWGWNDVNCLGPQRSVCEMMKIHL
• Function: C-type lectin receptor that binds carbohydrates mannose and fucose but also weakly interacts with N-acetylglucosamine (GlcNAc) in a Ca(2+)-dependent manner. Involved in regulating immune reactivity. Once triggered by antigen, it is internalized by clathrin-dependent endocytosis and delivers its antigenic cargo into the antigen presentation pathway resulting in cross-priming of CD8(+) T cells. This cross-presentation and cross-priming are enhanced by TLR7 and TLR8 agonists with increased expansion of the CD8(+) T cells, high production of IFNG and TNF with reduced levels of IL4, IL5 and IL13. In plasmacytoid dendritic cells, inhibits TLR9-mediated IFNA and TNF production. May be involved via its ITIM motif (immunoreceptor tyrosine-based inhibitory motifs) in the inhibition of B-cell-receptor-mediated calcium mobilization and protein tyrosine phosphorylation ; (Microbial infection) Involved in the interaction between HIV-1 virus and dendritic cells. Enhances HIV-1 binding/entry and virus infection. Requires ITIM motif-associated signal transduction pathway involving phosphatases PTPN6 and PTPN11, SYK, Src kinases and MAP kinases.
• Tissue Specificity: Expressed preferentially in hematopoietic tissues. Expressed in all circulating Ag-presenting cells such as dendritic cells, myeloid cells, monocytes, macrophages, B-cells and epidermal Langerhans cells (at protein level). Expressed in peripheral blood leukocytes, neutrophils, moderate quantities in spleen, lymph node, and bone marrow, and at very low levels in thymus.
• Reactome Pathway: Dectin-2 family (R-HSA-5621480)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Biomarker	[1]
Ulcerative colitis	DIS8K27O	Definitive	Biomarker	[1]
Allergy	DIS48ZAP	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[3]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-type lectin domain family 4 member A (CLEC4A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of C-type lectin domain family 4 member A (CLEC4A).	[5]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of C-type lectin domain family 4 member A (CLEC4A).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of C-type lectin domain family 4 member A (CLEC4A).	[8]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of C-type lectin domain family 4 member A (CLEC4A).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of C-type lectin domain family 4 member A (CLEC4A).	[10]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of C-type lectin domain family 4 member A (CLEC4A).	[2]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of C-type lectin domain family 4 member A (CLEC4A).	[7]

References

• [1] Single nucleotide polymorphisms in C-type lectin genes, clustered in the IBD2 and IBD6 susceptibility loci, may play a role in the pathogenesis of inflammatory bowel diseases.Eur J Gastroenterol Hepatol. 2012 Aug;24(8):965-70. doi: 10.1097/MEG.0b013e328354f3d5.
• [2] Evaluation of selected biomarkers for the detection of chemical sensitization in human skin: a comparative study applying THP-1, MUTZ-3 and primary dendritic cells in culture. Toxicol In Vitro. 2013 Sep;27(6):1659-69. doi: 10.1016/j.tiv.2013.04.009. Epub 2013 Apr 26.
• [3] Contribution of dendritic cell immunoreceptor (DCIR) polymorphisms in susceptibility of systemic lupus erythematosus and primary Sjogren's syndrome.Hum Immunol. 2015 Nov;76(11):808-11. doi: 10.1016/j.humimm.2015.09.040. Epub 2015 Sep 30.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] Evaluation of selected biomarkers for the detection of chemical sensitization in human skin: a comparative study applying THP-1, MUTZ-3 and primary dendritic cells in culture. Toxicol In Vitro. 2013 Sep;27(6):1659-69. doi: 10.1016/j.tiv.2013.04.009. Epub 2013 Apr 26.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.