Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWA7P10)

• DOT Name: Gasdermin-B (GSDMB)
• Synonyms: Gasdermin-like protein
• Gene Name: GSDMB
• Related Disease:
  Asthma
  Advanced cancer
  Allergic asthma
  Autoimmune disease
  Breast cancer
  Cervical cancer
  Crohn disease
  Gastric cancer
  Inflammatory bowel disease
  Irritable bowel syndrome
  Multiple sclerosis
  Neoplasm
  Pneumonia
  Pneumonitis
  Primary biliary cholangitis
  Respiratory disease
  Squamous cell carcinoma
  Systemic sclerosis
  Type-1 diabetes
  Ulcerative colitis
  Stomach cancer
  HER2/NEU overexpressing breast cancer
  Breast carcinoma
  Enterovirus infection
  Immune system disorder
  Rheumatoid arthritis
  Type-1/2 diabetes
• UniProt ID: GSDMB_HUMAN
• PDB ID: 5TIB; 5TJ2; 5TJ4; 7WJQ; 8EFP; 8ET1; 8ET2; 8GTJ; 8GTK; 8GTN
• Pfam ID: PF04598 ; PF17708
• Sequence:
  MFSVFEEITRIVVKEMDAGGDMIAVRSLVDADRFRCFHLVGEKRTFFGCRHYTTGLTLMD
  ILDTDGDKWLDELDSGLQGQKAEFQILDNVDSTGELIVRLPKEITISGSFQGFHHQKIKI
  SENRISQQYLATLENRKLKRELPFSFRSINTRENLYLVTETLETVKEETLKSDRQYKFWS
  QISQGHLSYKHKGQREVTIPPNRVLSYRVKQLVFPNKETMNIHFRGKTKSFPEEKDGASS
  CLGKSLGSEDSRNMKEKLEDMESVLKDLTEEKRKDVLNSLAKCLGKEDIRQDLEQRVSEV
  LISGELHMEDPDKPLLSSLFNAAGVLVEARAKAILDFLDALLELSEEQQFVAEALEKGTL
  PLLKDQVKSVMEQNWDELASSPPDMDYDPEARILCALYVVVSILLELAEGPTSVSS
• Function: [Gasdermin-B]: Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death. This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-B, N-terminal) binds to membranes and forms pores, triggering pyroptosis. Also acts as a regulator of epithelial cell repair independently of programmed cell death: translocates to the plasma membrane and promotes epithelial maintenance and repair by regulating PTK2/FAK-mediated phosphorylation of PDGFA ; [Gasdermin-B, N-terminal]: Pore-forming protein produced by cleavage by granzyme A (GZMA), which causes membrane permeabilization and pyroptosis in target cells of cytotoxic T and natural killer (NK) cells. Key downstream mediator of granzyme-mediated cell death: (1) granzyme A (GZMA), delivered to target cells from cytotoxic T- and NK-cells, (2) specifically cleaves Gasdermin-B to generate this form. After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis. The different isoforms recognize and bind different phospholipids on membranes, promoting cell death of different target cells ; [Isoform 4]: Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis. Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis. Recognizes and binds membrane inner leaflet lipids of human cells, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, and more weakly to phosphatidic acid. Also binds sufatide, a component of the apical membrane of epithelial cells ; [Isoform 6]: Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis of human cells. Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis ; [Isoform 1]: Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and specifically mediates cell death of Gram-negative bacteria in response to infection. Following cleavage and activation by granzyme A (GZMA), the N-terminal part recognizes and binds phospholipids found on Gram-negative bacterial membranes, such as lipid A and cariolipin, homooligomerizes within the bacterial membranes and forms pores, triggering pyroptosis followed by cell death. In contrast to isoform 4, does not bind to membrane inner leaflet lipids of host human cell, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate ; [Isoform 2]: Not able to trigger pyroptosis; [Isoform 3]: Not able to trigger pyroptosis.
• Tissue Specificity: In the gastrointestinal tract, expressed in proliferating cells, including in the basal cell layer of esophagus and in isthmus/neck of stomach.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[6]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[7]
Irritable bowel syndrome	DIS27206	Strong	Genetic Variation	[7]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Pneumonia	DIS8EF3M	Strong	Biomarker	[8]
Pneumonitis	DIS88E0K	Strong	Biomarker	[8]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[9]
Respiratory disease	DISGGAGJ	Strong	Genetic Variation	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[6]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[11]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[12]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[13]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[2]
HER2/NEU overexpressing breast cancer	DISYKID5	Disputed	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]
Enterovirus infection	DISH2UDP	Limited	Genetic Variation	[16]
Immune system disorder	DISAEGPH	Limited	Biomarker	[17]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[18]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[12]

14 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 Gasdermin-B (GSDMB).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gasdermin-B (GSDMB).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gasdermin-B (GSDMB).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gasdermin-B (GSDMB).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Gasdermin-B (GSDMB).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Gasdermin-B (GSDMB).	[24]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Gasdermin-B (GSDMB).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gasdermin-B (GSDMB).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gasdermin-B (GSDMB).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Gasdermin-B (GSDMB).	[29]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Gasdermin-B (GSDMB).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Gasdermin-B (GSDMB).	[31]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Gasdermin-B (GSDMB).	[32]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Gasdermin-B (GSDMB).	[33]

1 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 affects the methylation of Gasdermin-B (GSDMB).	[28]

References

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• [16] Genetic Determinants of Enterovirus Infections: Polymorphisms in Type 1 Diabetes and Innate Immune Genes in the MIDIA Study.Viral Immunol. 2015 Dec;28(10):556-63. doi: 10.1089/vim.2015.0067. Epub 2015 Oct 20.
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• [18] Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12.Am J Hum Genet. 2012 Mar 9;90(3):524-32. doi: 10.1016/j.ajhg.2012.01.010. Epub 2012 Feb 23.
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• [21] 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.
• [22] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [23] 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.
• [24] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [25] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [26] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [27] The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
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• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [31] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [32] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [33] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.