Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7P8ICY)

• DOT Name: C-type lectin domain family 4 member E (CLEC4E)
• Synonyms: C-type lectin superfamily member 9; Macrophage-inducible C-type lectin; MINCLE
• Gene Name: CLEC4E
• Related Disease:
  Nephropathy
  Acute myocardial infarction
  Alcoholic liver diseases
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Depression
  Fungal keratitis
  HIV infectious disease
  Keratitis
  Multiple sclerosis
  Myocardial infarction
  Neuralgia
  Subarachnoid hemorrhage
  Tuberculosis
  Lupus nephritis
  Pulmonary tuberculosis
  Arthritis
  Asthma
  Pneumocystis pneumonia
  Pulmonary disease
• UniProt ID: CLC4E_HUMAN
• PDB ID: 3WH2; 3WH3
• Pfam ID: PF00059
• Sequence:
  MNSSKSSETQCTERGCFSSQMFLWTVAGIPILFLSACFITRCVVTFRIFQTCDEKKFQLP
  ENFTELSCYNYGSGSVKNCCPLNWEYFQSSCYFFSTDTISWALSLKNCSAMGAHLVVINS
  QEEQEFLSYKKPKMREFFIGLSDQVVEGQWQWVDGTPLTKSLSFWDVGEPNNIATLEDCA
  TMRDSSNPRQNWNDVTCFLNYFRICEMVGINPLNKGKSL
• Function: Calcium-dependent lectin that acts as a pattern recognition receptor (PRR) of the innate immune system: recognizes damage-associated molecular patterns (DAMPs) of abnormal self and pathogen-associated molecular patterns (PAMPs) of bacteria and fungi. The PAMPs notably include mycobacterial trehalose 6,6'-dimycolate (TDM), a cell wall glycolipid with potent adjuvant immunomodulatory functions. Interacts with signaling adapter Fc receptor gamma chain/FCER1G to form a functional complex in myeloid cells. Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of FCER1G, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes. Also recognizes alpha-mannose residues on pathogenic fungi of the genus Malassezia and mediates macrophage activation. Through recognition of DAMPs released upon nonhomeostatic cell death, enables immune sensing of damaged self and promotes inflammatory cell infiltration into the damaged tissue.
• Tissue Specificity: Expressed in monocytes and macrophages.
• KEGG Pathway:
  C-type lectin receptor sig.ling pathway (hsa04625)
  Tuberculosis (hsa05152)
• Reactome Pathway: Dectin-2 family (R-HSA-5621480)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Alcoholic liver diseases	DISXEPHQ	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Fungal keratitis	DISA0XP5	Strong	Altered Expression	[7]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[8]
Keratitis	DISMFOEI	Strong	Altered Expression	[7]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[5]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[2]
Neuralgia	DISWO58J	Strong	Biomarker	[9]
Subarachnoid hemorrhage	DISI7I8Y	Strong	Biomarker	[6]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[10]
Lupus nephritis	DISCVGPZ	moderate	Biomarker	[11]
Pulmonary tuberculosis	DIS6FLUM	moderate	Genetic Variation	[12]
Arthritis	DIST1YEL	Disputed	Biomarker	[13]
Asthma	DISW9QNS	Limited	Altered Expression	[14]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[15]
Pulmonary disease	DIS6060I	Limited	Biomarker	[16]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	C-type lectin domain family 4 member E (CLEC4E) increases the response to substance of ANW-32821.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of C-type lectin domain family 4 member E (CLEC4E).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-type lectin domain family 4 member E (CLEC4E).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of C-type lectin domain family 4 member E (CLEC4E).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of C-type lectin domain family 4 member E (CLEC4E).	[20]
Tibolone	DM78XFG	Approved	Tibolone increases the expression of C-type lectin domain family 4 member E (CLEC4E).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of C-type lectin domain family 4 member E (CLEC4E).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of C-type lectin domain family 4 member E (CLEC4E).	[24]
Desmosterol	DMV8SUM	Investigative	Desmosterol increases the activity of C-type lectin domain family 4 member E (CLEC4E).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of C-type lectin domain family 4 member E (CLEC4E).	[23]

References

• [1] The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation.Kidney Int. 2017 Mar;91(3):587-602. doi: 10.1016/j.kint.2016.10.020. Epub 2016 Dec 22.
• [2] Microglial Mincle receptor in the PVN contributes to sympathetic hyperactivity in acute myocardial infarction rat.J Cell Mol Med. 2019 Jan;23(1):112-125. doi: 10.1111/jcmm.13890. Epub 2018 Oct 24.
• [3] Spliceosome-Associated Protein 130 Exacerbates Alcohol-Induced Liver Injury by Inducing NLRP3 Inflammasome-Mediated IL-1 in Mice.Am J Pathol. 2018 Apr;188(4):967-980. doi: 10.1016/j.ajpath.2017.12.010. Epub 2018 Jan 31.
• [4] Necrotic Cell Sensor Clec4e Promotes a Proatherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response.Circulation. 2016 Oct 4;134(14):1039-1051. doi: 10.1161/CIRCULATIONAHA.116.022668. Epub 2016 Sep 1.
• [5] C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation.J Clin Invest. 2020 Feb 3;130(2):838-852. doi: 10.1172/JCI125857.
• [6] Human albumin attenuates excessive innate immunity via inhibition of microglial Mincle/Syk signaling in subarachnoid hemorrhage.Brain Behav Immun. 2017 Feb;60:346-360. doi: 10.1016/j.bbi.2016.11.004. Epub 2016 Nov 11.
• [7] The role of Mincle in innate immune to fungal keratitis.J Infect Dev Ctries. 2017 Jan 30;11(1):89-97. doi: 10.3855/jidc.7570.
• [8] Impact of Aging and HIV Infection on the Function of the C-Type Lectin Receptor MINCLE in Monocytes.J Gerontol A Biol Sci Med Sci. 2019 May 16;74(6):794-801. doi: 10.1093/gerona/gly209.
• [9] Essential roles of C-type lectin Mincle in induction of neuropathic pain in mice.Sci Rep. 2019 Jan 29;9(1):872. doi: 10.1038/s41598-018-37318-8.
• [10] Aryl Trehalose Derivatives as Vaccine Adjuvants for Mycobacterium tuberculosis.J Med Chem. 2020 Jan 9;63(1):309-320. doi: 10.1021/acs.jmedchem.9b01598. Epub 2019 Dec 20.
• [11] Silencing of renal DNaseI in murine lupus nephritis imposes exposure of large chromatin fragments and activation of Toll like receptors and the Clec4e.PLoS One. 2012;7(3):e34080. doi: 10.1371/journal.pone.0034080. Epub 2012 Mar 30.
• [12] Association between CLEC4E gene polymorphism of mincle and pulmonary tuberculosis infection in a northern Chinese population.Gene. 2019 Aug 20;710:24-29. doi: 10.1016/j.gene.2019.05.011. Epub 2019 May 7.
• [13] Macrophage-inducible C-type lectin is associated with anti-cyclic citrullinated peptide antibodies-positive rheumatoid arthritis in men.Chin Med J (Engl). 2012 Sep;125(17):3115-9.
• [14] Ca(2+) and innate immune pathways are activated and differentially expressed in childhood asthma phenotypes.Pediatr Allergy Immunol. 2018 Dec;29(8):823-833. doi: 10.1111/pai.12971. Epub 2018 Oct 9.
• [15] The Interaction of Pneumocystis with the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense against Infection.J Immunol. 2017 May 1;198(9):3515-3525. doi: 10.4049/jimmunol.1600744. Epub 2017 Mar 15.
• [16] Blood gene expression profiling detects silica exposure and toxicity.Toxicol Sci. 2011 Aug;122(2):253-64. doi: 10.1093/toxsci/kfr125. Epub 2011 May 19.
• [17] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women. Thromb Res. 2012 Jul;130(1):45-51. doi: 10.1016/j.thromres.2011.12.009. Epub 2012 Jan 2.
• [22] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [25] Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses. J Biol Chem. 2015 Oct 16;290(42):25322-32. doi: 10.1074/jbc.M115.645234. Epub 2015 Aug 20.
• [26] Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses. J Biol Chem. 2015 Oct 16;290(42):25322-32. doi: 10.1074/jbc.M115.645234. Epub 2015 Aug 20.