Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEJ7ROA)

• DOT Name: NLR family member X1 (NLRX1)
• Synonyms: Caterpiller protein 11.3; CLR11.3; Nucleotide-binding oligomerization domain protein 5; Nucleotide-binding oligomerization domain protein 9
• Gene Name: NLRX1
• UniProt ID: NLRX1_HUMAN
• PDB ID: 3UN9
• Pfam ID: PF13516 ; PF05729 ; PF21402
• Sequence:
  MRWGHHLPRASWGSGFRRALQRPDDRIPFLIHWSWPLQGERPFGPPRAFIRHHGSSVDSA
  PPPGRHGRLFPSASATEAIQRHRRNLAEWFSRLPREERQFGPTFALDTVHVDPVIRESTP
  DELLRPPAELALEHQPPQAGLPPLALSQLFNPDACGRRVQTVVLYGTVGTGKSTLVRKMV
  LDWCYGRLPAFELLIPFSCEDLSSLGPAPASLCQLVAQRYTPLKEVLPLMAAAGSHLLFV
  LHGLEHLNLDFRLAGTGLCSDPEEPQEPAAIIVNLLRKYMLPQASILVTTRPSAIGRIPS
  KYVGRYGEICGFSDTNLQKLYFQLRLNQPYCGYAVGGSGVSATPAQRDHLVQMLSRNLEG
  HHQIAAACFLPSYCWLVCATLHFLHAPTPAGQTLTSIYTSFLRLNFSGETLDSTDPSNLS
  LMAYAARTMGKLAYEGVSSRKTYFSEEDVCGCLEAGIRTEEEFQLLHIFRRDALRFFLAP
  CVEPGRAGTFVFTVPAMQEYLAALYIVLGLRKTTLQKVGKEVAELVGRVGEDVSLVLGIM
  AKLLPLRALPLLFNLIKVVPRVFGRMVGKSREAVAQAMVLEMFREEDYYNDDVLDQMGAS
  ILGVEGPRRHPDEPPEDEVFELFPMFMGGLLSAHNRAVLAQLGCPIKNLDALENAQAIKK
  KLGKLGRQVLPPSELLDHLFFHYEFQNQRFSAEVLSSLRQLNLAGVRMTPVKCTVVAAVL
  GSGRHALDEVNLASCQLDPAGLRTLLPVFLRARKLGLQLNSLGPEACKDLRDLLLHDQCQ
  ITTLRLSNNPLTAAGVAVLMEGLAGNTSVTHLSLLHTGLGDEGLELLAAQLDRNRQLQEL
  NVAYNGAGDTAALALARAAREHPSLELLHLYFNELSSEGRQVLRDLGGAAEGGARVVVSL
  TEGTAVSEYWSVILSEVQRNLNSWDRARVQRHLELLLRDLEDSRGATLNPWRKAQLLRVE
  GEVRALLEQLGSSGS
• Function: Participates in antiviral signaling. Acts as a negative regulator of MAVS-mediated antiviral responses, through the inhibition of the virus-induced RLH (RIG-like helicase)-MAVS interaction. Instead, promotes autophagy by interacting with TUFM and subsequently recruiting the autophagy-related proteins ATG5 and ATG12. Regulates also MAVS-dependent NLRP3 inflammasome activation to attenuate apoptosis. Has no inhibitory function on NF-kappa-B signaling pathway, but enhances NF-kappa-B and JUN N-terminal kinase dependent signaling through the production of reactive oxygen species. Regulates viral mediated-inflammation and energy metabolism in a sex-dependent manner. In females, prevents uncontrolled inflammation and energy metabolism and thus, may contribute to the sex differences observed in infectious and inflammatory diseases.
• Tissue Specificity: Ubiquitously expressed. Strongest expression in mammary gland, heart and muscle. Detected in HeLa, HEK293T, THP-1, HL-60, Raji and Jurkat cell lines (at protein level).
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Influenza A (hsa05164)
• Reactome Pathway:
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Regulation of NF-kappa B signaling (R-HSA-9758274)
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of NLR family member X1 (NLRX1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NLR family member X1 (NLRX1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NLR family member X1 (NLRX1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NLR family member X1 (NLRX1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of NLR family member X1 (NLRX1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NLR family member X1 (NLRX1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NLR family member X1 (NLRX1).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of NLR family member X1 (NLRX1).	[8]
Bupivacaine	DM4PRFC	Approved	Bupivacaine decreases the expression of NLR family member X1 (NLRX1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NLR family member X1 (NLRX1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NLR family member X1 (NLRX1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NLR family member X1 (NLRX1).	[14]

2 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 decreases the methylation of NLR family member X1 (NLRX1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NLR family member X1 (NLRX1).	[12]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [9] LncRNA SNHG12 ameliorates bupivacaine-induced neurotoxicity by sponging miR-497-5p to upregulate NLRX1. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221089001. doi: 10.1177/09603271221089001.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.