Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBE0PLF)

• DOT Name: Paired immunoglobulin-like type 2 receptor alpha (PILRA)
• Synonyms: Cell surface receptor FDF03; Inhibitory receptor PILR-alpha
• Gene Name: PILRA
• Related Disease:
  Age-related macular degeneration
  Alzheimer disease
  Herpes simplex infection
  Neovascular age-related macular degeneration
  46,XY sex reversal 2
  Charcot-Marie-Tooth disease type 3
  Colitis
  Inflammatory bowel disease
• UniProt ID: PILRA_HUMAN
• PDB ID: 3WUZ; 3WV0; 4NFB; 5XO2; 5XOF
• Pfam ID: PF07686
• Sequence:
  MGRPLLLPLLPLLLPPAFLQPSGSTGSGPSYLYGVTQPKHLSASMGGSVEIPFSFYYPWE
  LATAPDVRISWRRGHFHRQSFYSTRPPSIHKDYVNRLFLNWTEGQKSGFLRISNLQKQDQ
  SVYFCRVELDTRSSGRQQWQSIEGTKLSITQAVTTTTQRPSSMTTTWRLSSTTTTTGLRV
  TQGKRRSDSWHISLETAVGVAVAVTVLGIMILGLICLLRWRRRKGQQRTKATTPAREPFQ
  NTEEPYENIRNEGQNTDPKLNPKDDGIVYASLALSSSTSPRAPPSHRPLKSPQNETLYSV
  LKA
• Function: Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRA is thought to act as a cellular signaling inhibitory receptor by recruiting cytoplasmic phosphatases like PTPN6/SHP-1 and PTPN11/SHP-2 via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Receptor for PIANP; (Microbial infection) Acts as an entry co-receptor for herpes simplex virus 1.
• Tissue Specificity: Predominantly detected in hemopoietic tissues and is expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes. Also strongly expressed by dendritic cells (DC); preferentially by CD14+/CD1a- DC derived from CD34+ progenitors. Also expressed by CD11c+ blood and tonsil DC, but not by CD11c- DC precursors.
• KEGG Pathway:
  Virion - Herpesvirus (hsa03266)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[3]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[1]
46,XY sex reversal 2	DIS0USUN	Limited	Biomarker	[4]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[4]
Colitis	DISAF7DD	Limited	Biomarker	[4]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[4]

13 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 Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[10]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[8]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Paired immunoglobulin-like type 2 receptor alpha (PILRA).	[14]

References

• [1] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [2] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [3] Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease.PLoS Genet. 2018 Nov 2;14(11):e1007427. doi: 10.1371/journal.pgen.1007427. eCollection 2018 Nov.
• [4] Negative regulation of DSS-induced experimental colitis by PILR.Int Immunol. 2015 Jun;27(6):307-14. doi: 10.1093/intimm/dxv004. Epub 2015 Feb 20.
• [5] 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.
• [6] 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.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [10] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [14] 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.