Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT86QUI8)

DOT Name	Interferon-inducible protein AIM2 (AIM2)
Synonyms	Absent in melanoma 2
Gene Name	AIM2
Related Disease	Abdominal aortic aneurysm ( ) Adult glioblastoma ( ) Advanced cancer ( ) Alzheimer disease ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Autoimmune disease ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Cervical cancer ( ) Cervical carcinoma ( ) Chronic hepatitis B virus infection ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal neoplasm ( ) Cytomegalovirus infection ( ) Glioblastoma multiforme ( ) Glioma ( ) Hepatitis B virus infection ( ) Hepatocellular carcinoma ( ) Lupus ( ) Multiple sclerosis ( ) Neoplasm ( ) Nervous system inflammation ( ) Non-insulin dependent diabetes ( ) Psoriasis ( ) Renal cell carcinoma ( ) Skin disease ( ) Squamous cell carcinoma ( ) Systemic lupus erythematosus ( ) Tuberculosis ( ) Type-1/2 diabetes ( ) Non-small-cell lung cancer ( ) Obesity ( ) Pancreatic cancer ( ) Prostate cancer ( ) Prostate carcinoma ( ) Bacterial infection ( ) Chronic obstructive pulmonary disease ( ) Enterovirus infection ( ) Inflammatory bowel disease ( ) Lupus nephritis ( ) Melanoma ( )
UniProt ID	AIM2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3RN2; 3RN5; 3VD8; 4O7Q; 6MB2; 7K3R
Pfam ID	PF02760 ; PF02758
Sequence	MESKYKEILLLTGLDNITDEELDRFKFFLSDEFNIATGKLHTANRIQVATLMIQNAGAVS AVMKTIRIFQKLNYMLLAKRLQEEKEKVDKQYKSVTKPKPLSQAEMSPAASAAIRNDVAK QRAAPKVSPHVKPEQKQMVAQQESIREGFQKRCLPVMVLKAKKPFTFETQEGKQEMFHAT VATEKEFFFVKVFNTLLKDKFIPKRIIIIARYYRHSGFLEVNSASRVLDAESDQKVNVPL NIIRKAGETPKINTLQTQPLGTIVNGLFVVQKVTEKKKNILFDLSDNTGKMEVLGVRNED TMKCKEGDKVRLTFFTLSKNGEKLQLTSGVHSTIKVIKAKKKT
Function	Sensor component of the AIM2 inflammasome, which mediates inflammasome activation in response to the presence of double-stranded DNA (dsDNA) in the cytosol, leading to subsequent pyroptosis. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. Acts as a recognition receptor (PRR): specifically recognizes and binds dsDNA in the cytosol, and mediates the formation of the inflammasome polymeric complex composed of AIM2, CASP1 and PYCARD/ASC. Recruitment of pro-caspase-1 (proCASP1) to the AIM2 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion. In some cells, CASP1 activation mediates cleavage and activation of GSDMD, triggering pyroptosis without promoting cytokine secretion. Detects cytosolic dsDNA of viral and bacterial origin in a non-sequence-specific manner. Involved in the DNA damage response caused by acute ionizing radiation by mediating pyroptosis of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks. Mechanistically, AIM2 senses DNA damage in the nucleus to mediate inflammasome assembly and inflammatory cell death. Also acts as a regulator of neurodevelopment via its role in the DNA damage response: acts by promoting neural cell death in response to DNA damage in the developing brain, thereby purging genetically compromised cells of the central nervous system. Pyroptosis mediated by the AIM2 inflammasome in response to DNA damage is dependent on GSDMD without involving IL1B and IL18 cytokine secretion. Also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection. Can also trigger PYCARD/ASC-dependent, caspase-1-independent cell death that involves caspase-8 (CASP8); Also acts as a tumor suppressor independently of its role in inflammatory response. Able to suppress overt cell proliferation in enterocytes: restricts stem cell proliferation in the intestinal mucosa in an inflammasome-independent manner, contributing to a decrease in the likelihood of colorectal cancer development. AIM2 suppresses cell proliferation by inhibiting phosphorylation of AKT1 at 'Ser-473', preventing AKT1 activation and AKT-mTOR signaling pathway. Inhibits AKT1 phosphorylation both by inhibiting the activity of PRKDC/DNA-PK kinase and promoting dephosphorylation by PP2A phosphatase. Also acts as a key regulator of regulatory T-cells (Treg) homeostasis by promoting their stability: acts by preventing AKT1 activation. Its role in Treg homeostasis is important to restain autoimmune diseases.
Tissue Specificity	Expressed in spleen, small intestine, peripheral blood leukocytes, and testis.
KEGG Pathway	NOD-like receptor sig.ling pathway (hsa04621 ) Cytosolic D.-sensing pathway (hsa04623 )
Reactome Pathway	The AIM2 inflammasome (R-HSA-844615 ) Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Posttranslational Modification	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Cervical cancer	DISFSHPF	Strong	Biomarker	[9]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[9]
Chronic hepatitis B virus infection	DISHL4NT	Strong	Altered Expression	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[11]
Colon cancer	DISVC52G	Strong	Biomarker	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[13]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Strong	Posttranslational Modification	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Lupus	DISOKJWA	Strong	Genetic Variation	[16]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[17]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[19]
Psoriasis	DIS59VMN	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[11]
Skin disease	DISDW8R6	Strong	Biomarker	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[21]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[16]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[22]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[23]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[24]
Obesity	DIS47Y1K	moderate	Biomarker	[25]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[26]
Prostate cancer	DISF190Y	moderate	Biomarker	[27]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[27]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[28]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[29]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[30]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[31]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[32]
Melanoma	DIS1RRCY	Limited	Biomarker	[33]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Interferon-inducible protein AIM2 (AIM2) affects the response to substance of Methotrexate.	[40]
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6 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 Interferon-inducible protein AIM2 (AIM2).	[34]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Interferon-inducible protein AIM2 (AIM2).	[35]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Interferon-inducible protein AIM2 (AIM2).	[36]
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin increases the expression of Interferon-inducible protein AIM2 (AIM2).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interferon-inducible protein AIM2 (AIM2).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Interferon-inducible protein AIM2 (AIM2).	[35]
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⏷ Show the Full List of 6 Drug(s)

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 Interferon-inducible protein AIM2 (AIM2).	[38]
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References

1	AIM2 levels and DNA-triggered inflammasome response are increased in peripheral leukocytes of patients with abdominal aortic aneurysm.Inflamm Res. 2019 Apr;68(4):337-345. doi: 10.1007/s00011-019-01212-4. Epub 2019 Feb 13.
2	Differential Expression Profile of NLRs and AIM2 in Glioma and Implications for NLRP12 in Glioblastoma.Sci Rep. 2019 Jun 11;9(1):8480. doi: 10.1038/s41598-019-44854-4.
3	Absent in melanoma 2 suppresses epithelial-mesenchymal transition via Akt and inflammasome pathways in human colorectal cancer cells.J Cell Biochem. 2019 Oct;120(10):17744-17756. doi: 10.1002/jcb.29040. Epub 2019 Jun 18.
4	Type I interferon (IFN)-inducible Absent in Melanoma 2 proteins in neuroinflammation: implications for Alzheimer's disease.J Neuroinflammation. 2019 Nov 26;16(1):236. doi: 10.1186/s12974-019-1639-5.
5	AIM2 accelerates the atherosclerotic plaque progressions in ApoE-/- mice.Biochem Biophys Res Commun. 2018 Apr 6;498(3):487-494. doi: 10.1016/j.bbrc.2018.03.005. Epub 2018 Mar 3.
6	EFLA 945 restricts AIM2 inflammasome activation by preventing DNA entry for psoriasis treatment.Cytokine. 2020 Mar;127:154951. doi: 10.1016/j.cyto.2019.154951. Epub 2019 Dec 11.
7	Ribosomal DNA as DAMPs Signal for MCF7 Cancer Cells.Front Oncol. 2019 May 30;9:445. doi: 10.3389/fonc.2019.00445. eCollection 2019.
8	AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model.Mol Cancer Ther. 2006 Jan;5(1):1-7. doi: 10.1158/1535-7163.MCT-05-0310.
9	Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense.Oncogene. 2018 Sep;37(38):5191-5204. doi: 10.1038/s41388-018-0339-4. Epub 2018 May 29.
10	Differential Activation of NLRP3, AIM2, and IFI16 Inflammasomes in Humans with Acute and Chronic Hepatitis B.Viral Immunol. 2018 Nov;31(9):639-645. doi: 10.1089/vim.2018.0058. Epub 2018 Sep 15.
11	H1/pAIM2 nanoparticles exert anti-tumour effects that is associated with the inflammasome activation in renal carcinoma.J Cell Mol Med. 2018 Nov;22(11):5670-5681. doi: 10.1111/jcmm.13842. Epub 2018 Aug 30.
12	Compensation of loss of protein function in microsatellite-unstable colon cancer cells (HCT116): a gene-dependent effect on the cell surface glycan profile.Glycobiology. 2009 Jul;19(7):726-34. doi: 10.1093/glycob/cwp040. Epub 2009 Mar 17.
13	Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers.Oncogene. 2012 Mar 8;31(10):1242-53. doi: 10.1038/onc.2011.320. Epub 2011 Aug 1.
14	Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1 Protein during Virion-Mediated Activation of the AIM2 Inflammasome.mBio. 2019 Feb 12;10(1):e02510-18. doi: 10.1128/mBio.02510-18.
15	AIM2 deficiency reduces the development of hepatocellular carcinoma in mice.Int J Cancer. 2018 Dec 1;143(11):2997-3007. doi: 10.1002/ijc.31827. Epub 2018 Oct 9.
16	Inhibition of AIM2 inflammasome activation by a novel transcript isoform of IFI16.EMBO Rep. 2018 Oct;19(10):e45737. doi: 10.15252/embr.201845737. Epub 2018 Aug 13.
17	Role of Inflammasomes in Neuroimmune and Neurodegenerative Diseases: A Systematic Review.Mediators Inflamm. 2018 Apr 17;2018:1549549. doi: 10.1155/2018/1549549. eCollection 2018.
18	Low expression of AIM2 combined with high expression of pSTAT3 is associated with poor prognosis in hypopharyngeal squamous cell carcinoma.Oncol Rep. 2019 Apr;41(4):2396-2408. doi: 10.3892/or.2019.7029. Epub 2019 Feb 25.
19	Circulating Cell-Free mtDNA Contributes to AIM2 Inflammasome-Mediated Chronic Inflammation in Patients with Type 2 Diabetes.Cells. 2019 Apr 8;8(4):328. doi: 10.3390/cells8040328.
20	Role of AIM2 inflammasome in inflammatory diseases, cancer and infection.Eur J Immunol. 2019 Nov;49(11):1998-2011. doi: 10.1002/eji.201848070. Epub 2019 Aug 14.
21	Overexpression of absent in melanoma 2 in oral squamous cell carcinoma contributes to tumor progression.Biochem Biophys Res Commun. 2019 Jan 29;509(1):82-88. doi: 10.1016/j.bbrc.2018.12.066. Epub 2018 Dec 23.
22	Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil.Int J Infect Dis. 2020 Mar;92:21-28. doi: 10.1016/j.ijid.2019.12.013. Epub 2019 Dec 13.
23	AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model.Life Sci. 2019 Mar 15;221:249-258. doi: 10.1016/j.lfs.2019.02.035. Epub 2019 Feb 18.
24	Decrease of AIM2 mediated by luteolin contributes to non-small cell lung cancer treatment.Cell Death Dis. 2019 Mar 4;10(3):218. doi: 10.1038/s41419-019-1447-y.
25	Deficiency in AIM2 induces inflammation and adipogenesis in white adipose tissue leading to obesity and insulin resistance.Diabetologia. 2019 Dec;62(12):2325-2339. doi: 10.1007/s00125-019-04983-x. Epub 2019 Sep 11.
26	PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism.Dev Cell. 2018 Aug 20;46(4):441-455.e8. doi: 10.1016/j.devcel.2018.07.012. Epub 2018 Aug 9.
27	AIM2, an IFN-inducible cytosolic DNA sensor, in the development of benign prostate hyperplasia and prostate cancer.Mol Cancer Res. 2013 Oct;11(10):1193-202. doi: 10.1158/1541-7786.MCR-13-0145. Epub 2013 Jul 17.
28	GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation.Thorax. 2020 Mar;75(3):227-236. doi: 10.1136/thoraxjnl-2019-213571. Epub 2019 Dec 10.
29	AIM2 Inflammasome Activation Leads to IL-1 and TGF- Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells.Front Pharmacol. 2019 Mar 15;10:257. doi: 10.3389/fphar.2019.00257. eCollection 2019.
30	RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5' Nontranslated Regions.J Virol. 2018 Feb 26;92(6):e01914-17. doi: 10.1128/JVI.01914-17. Print 2018 Mar 15.
31	The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway.Cell Mol Immunol. 2017 Jan;14(1):127-142. doi: 10.1038/cmi.2016.35. Epub 2016 Aug 15.
32	Interferon (IFN)-inducible Absent in Melanoma 2 proteins in the negative regulation of the type I IFN response: Implications for lupus nephritis.Cytokine. 2020 Aug;132:154682. doi: 10.1016/j.cyto.2019.03.008. Epub 2019 Mar 20.
33	Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis.J Vasc Surg. 2014 Mar;59(3):794-803. doi: 10.1016/j.jvs.2013.03.048. Epub 2013 Jun 21.
34	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.
35	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
36	The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
37	Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells. Chem Biol Interact. 2021 May 1;340:109434. doi: 10.1016/j.cbi.2021.109434. Epub 2021 Mar 6.
38	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.
39	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.
40	Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.