Details of Drug Off-Target (DOT)

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

• DOT Name: NACHT, LRR and PYD domains-containing protein 9 (NLRP9)
• Synonyms: Nucleotide-binding oligomerization domain protein 6; PYRIN and NACHT-containing protein 12
• Gene Name: NLRP9
• Related Disease:
  Transitional cell carcinoma
  Urothelial carcinoma
• UniProt ID: NLRP9_HUMAN
• PDB ID: 6Z2G; 7BSO
• Pfam ID: PF13516 ; PF05729 ; PF17776 ; PF17779 ; PF02758
• Sequence:
  MAESFFSDFGLLWYLKELRKEEFWKFKELLKQPLEKFELKPIPWAELKKASKEDVAKLLD
  KHYPGKQAWEVTLNLFLQINRKDLWTKAQEEMRNKLNPYRKHMKETFQLIWEKETCLHVP
  EHFYKETMKNEYKELNDAYTAAARRHTVVLEGPDGIGKTTLLRKVMLDWAEGNLWKDRFT
  FVFFLNVCEMNGIAETSLLELLSRDWPESSEKIEDIFSQPERILFIMDGFEQLKFNLQLK
  ADLSDDWRQRQPMPIILSSLLQKKMLPESSLLIALGKLAMQKHYFMLRHPKLIKLLGFSE
  SEKKSYFSYFFGEKSKALKVFNFVRDNGPLFILCHNPFTCWLVCTCVKQRLERGEDLEIN
  SQNTTYLYASFLTTVFKAGSQSFPPKVNRARLKSLCALAAEGIWTYTFVFSHGDLRRNGL
  SESEGVMWVGMRLLQRRGDCFAFMHLCIQEFCAAMFYLLKRPKDDPNPAIGSITQLVRAS
  VVQPQTLLTQVGIFMFGISTEEIVSMLETSFGFPLSKDLKQEITQCLESLSQCEADREAI
  AFQELFIGLFETQEKEFVTKVMNFFEEVFIYIGNIEHLVIASFCLKHCQHLTTLRMCVEN
  IFPDDSGCISDYNEKLVYWRELCSMFITNKNFQILDMENTSLDDPSLAILCKALAQPVCK
  LRKLIFTSVYFGHDSELFKAVLHNPHLKLLSLYGTSLSQSDIRHLCETLKHPMCKIEELI
  LGKCDISSEVCEDIASVLACNSKLKHLSLVENPLRDEGMTLLCEALKHSHCALERLMLMY
  CCLTSVSCDSISEVLLCSKSLSLLDLGSNALEDNGVASLCAALKHPGCSIRELWLMGCFL
  TSDSCKDIAAVLICNGKLKTLKLGHNEIGDTGVRQLCAALQHPHCKLECLGLQTCPITRA
  CCDDIAAALIACKTLRSLNLDWIALDADAVVVLCEALSHPDCALQMLGLHKSGFDEETQK
  ILMSVEEKIPHLTISHGPWIDEEYKIRGVLL
• Function: As the sensor component of the NLRP9 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens, including rotavirus, initiates the formation of the inflammasome polymeric complex, made of NLRP9, PYCARD and CASP1. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and release in the extracellular milieu. The active cytokines stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. NLRP9 inflammasome activation may be initiated by DHX9 interaction with viral double-stranded RNA (dsRNA), preferentially to short dsRNA segments.
• Tissue Specificity: Expressed in ileum intestinal epithelial cells. Not detected in peripheral blood mononuclear cells . Expressed in cerebral endothelial cells and, at much lower levels, in brain pericytes .

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[1]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of NACHT, LRR and PYD domains-containing protein 9 (NLRP9).	[2]

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 NACHT, LRR and PYD domains-containing protein 9 (NLRP9).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NACHT, LRR and PYD domains-containing protein 9 (NLRP9).	[4]

References

• [1] Characterization of inflammasome-related genes in urine sediments of patients receiving intravesical BCG therapy.Urol Oncol. 2017 Dec;35(12):674.e19-674.e24. doi: 10.1016/j.urolonc.2017.08.004. Epub 2017 Sep 6.
• [2] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [3] 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.
• [4] 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.