Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9WNOKY)

• DOT Name: Transforming growth factor beta activator LRRC33 (NRROS)
• Synonyms: Leucine-rich repeat-containing protein 33; Negative regulator of reactive oxygen species
• Gene Name: NRROS
• Related Disease:
  Seizures, early-onset, with neurodegeneration and brain calcifications
  Acute myelogenous leukaemia
  Asthma
• UniProt ID: LRC33_HUMAN
• Pfam ID: PF00560 ; PF13516 ; PF13855
• Sequence:
  MELLPLWLCLGFHFLTVGWRNRSGTATAASQGVCKLVGGAADCRGQSLASVPSSLPPHAR
  MLTLDANPLKTLWNHSLQPYPLLESLSLHSCHLERISRGAFQEQGHLRSLVLGDNCLSEN
  YEETAAALHALPGLRRLDLSGNALTEDMAALMLQNLSSLRSVSLAGNTIMRLDDSVFEGL
  ERLRELDLQRNYIFEIEGGAFDGLAELRHLNLAFNNLPCIVDFGLTRLRVLNVSYNVLEW
  FLATGGEAAFELETLDLSHNQLLFFPLLPQYSKLRTLLLRDNNMGFYRDLYNTSSPREMV
  AQFLLVDGNVTNITTVSLWEEFSSSDLADLRFLDMSQNQFQYLPDGFLRKMPSLSHLNLH
  QNCLMTLHIREHEPPGALTELDLSHNQLSELHLAPGLASCLGSLRLFNLSSNQLLGVPPG
  LFANARNITTLDMSHNQISLCPLPAASDRVGPPSCVDFRNMASLRSLSLEGCGLGALPDC
  PFQGTSLTYLDLSSNWGVLNGSLAPLQDVAPMLQVLSLRNMGLHSSFMALDFSGFGNLRD
  LDLSGNCLTTFPRFGGSLALETLDLRRNSLTALPQKAVSEQLSRGLRTIYLSQNPYDCCG
  VDGWGALQHGQTVADWAMVTCNLSSKIIRVTELPGGVPRDCKWERLDLGLLYLVLILPSC
  LTLLVACTVIVLTFKKPLLQVIKSRCHWSSVY
• Function: Key regulator of transforming growth factor beta-1 (TGFB1) specifically required for microglia function in the nervous system. Required for activation of latent TGF-beta-1 in macrophages and microglia: associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGFB1, and regulates integrin-dependent activation of TGF-beta-1. TGF-beta-1 activation mediated by LRRC33/NRROS is highly localized: there is little spreading of TGF-beta-1 activated from one microglial cell to neighboring microglia, suggesting the existence of localized and selective activation of TGF-beta-1 by LRRC33/NRROS. Indirectly plays a role in Toll-like receptor (TLR) signaling: ability to inhibit TLR-mediated NF-kappa-B activation and cytokine production is probably a consequence of its role in TGF-beta-1 signaling.
• Tissue Specificity: Mainly expressed in cells of hematopoietic origin . Highly expressed in bone marrow, thymus, liver, lung, intestine and spleen . In the brain, highly expressed in microglia .
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Seizures, early-onset, with neurodegeneration and brain calcifications	DIS7SGLK	Definitive	Autosomal recessive	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Asthma	DISW9QNS	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transforming growth factor beta activator LRRC33 (NRROS).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transforming growth factor beta activator LRRC33 (NRROS).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[9]
Scriptaid	DM9JZ21	Preclinical	Scriptaid decreases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[8]
Oxamflatin	DM1TG3C	Terminated	Oxamflatin decreases the expression of Transforming growth factor beta activator LRRC33 (NRROS).	[8]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] LRRC33 is a novel binding and potential regulating protein of TGF-1 function in human acute myeloid leukemia cells.PLoS One. 2019 Oct 10;14(10):e0213482. doi: 10.1371/journal.pone.0213482. eCollection 2019.
• [3] A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases.Nat Genet. 2018 Jun;50(6):857-864. doi: 10.1038/s41588-018-0121-0. Epub 2018 May 21.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.