Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMND7IR)

• DOT Name: GTPase IMAP family member 5 (GIMAP5)
• Synonyms: Immune-associated nucleotide-binding protein 5; Immunity-associated nucleotide 4-like 1 protein; Immunity-associated nucleotide 5 protein; IAN-5; hIAN5; Immunity-associated protein 3
• Gene Name: GIMAP5
• Related Disease:
  Advanced cancer
  Hepatocellular carcinoma
  Neoplasm
  Portal hypertension, noncirrhotic, 2
  Systemic lupus erythematosus
  Type-1 diabetes
  Type-1/2 diabetes
  Asthma
  Autoimmune disease
  Colitis
  Immune system disorder
• UniProt ID: GIMA5_HUMAN
• PDB ID: 6Z3E
• Pfam ID: PF04548
• Sequence:
  MGGFQRGKYGTMAEGRSEDNLSATPPALRIILVGKTGCGKSATGNSILGQPVFESKLRAQ
  SVTRTCQVKTGTWNGRKVLVVDTPSIFESQADTQELYKNIGDCYLLSAPGPHVLLLVIQL
  GRFTAQDTVAIRKVKEVFGTGAMRHVVILFTHKEDLGGQALDDYVANTDNCSLKDLVREC
  ERRYCAFNNWGSVEEQRQQQAELLAVIERLGREREGSFHSNDLFLDAQLLQRTGAGACQE
  DYRQYQAKVEWQVEKHKQELRENESNWAYKALLRVKHLMLLHYEIFVFLLLCSILFFIIF
  LFIFHYI
• Function: Plays a role in T lymphocyte development and the optimal generation of CD4/CD8 double-positive thymocytes. Inhibitor of GSK3A, possibly by sequestering GSK3A in cytoplasmic vesicles and impairing its translocation to the nucleus. Consequently, impairs GSK3A-dependent transcriptional program and regulation of the DNA damage response occurring during T cells proliferation. Required for the survival of peripheral T cells, natural killer (NK) and NK T-cell development and the maintenance of normal liver function. May promote the survival of mature T lymphocytes upon cytokine withdrawal. May regulate Ca(2+) homeostasis by modulating lysosomal Ca(2+) stores, preventing its accumulation in the absence of T cell activation. May play a role in mitochondrial DNA segregation in hematopoietic tissues. Is a regulator of liver endothelial cell homeostasis.
• Tissue Specificity: Widely expressed with high levels in lymph node and spleen . High expression found in T lymphocytes, including CD4 and CD8-positive T-cells, and monocytes . Very low expression levels in B-lymphocytes .

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Portal hypertension, noncirrhotic, 2	DISYAMWU	Strong	Autosomal recessive	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[4]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[5]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[6]
Asthma	DISW9QNS	Limited	Genetic Variation	[7]
Autoimmune disease	DISORMTM	Limited	Biomarker	[8]
Colitis	DISAF7DD	Limited	Biomarker	[8]
Immune system disorder	DISAEGPH	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of GTPase IMAP family member 5 (GIMAP5).	[9]

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 increases the methylation of GTPase IMAP family member 5 (GIMAP5).	[10]

References

• [1] hIan5: the human ortholog to the rat Ian4/Iddm1/lyp is a new member of the Ian family that is overexpressed in B-cell lymphoid malignancies.Genes Immun. 2004 Mar;5(2):109-16. doi: 10.1038/sj.gene.6364044.
• [2] Dysregulation of GTPase IMAP family members in hepatocellular cancer.Mol Med Rep. 2016 Nov;14(5):4119-4123. doi: 10.3892/mmr.2016.5764. Epub 2016 Sep 22.
• [3] GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension. J Exp Med. 2021 Jul 5;218(7):e20201745. doi: 10.1084/jem.20201745. Epub 2021 May 6.
• [4] IAN5 polymorphisms are associated with systemic lupus erythematosus.Lupus. 2009 Oct;18(12):1045-52. doi: 10.1177/0961203309106830.
• [5] GIMAP GTPase family genes: potential modifiers in autoimmune diabetes, asthma, and allergy.J Immunol. 2015 Jun 15;194(12):5885-94. doi: 10.4049/jimmunol.1500016. Epub 2015 May 11.
• [6] Type 1 diabetes in BioBreeding rats is critically linked to an imbalance between Th17 and regulatory T cells and an altered TCR repertoire.J Immunol. 2010 Aug 15;185(4):2285-94. doi: 10.4049/jimmunol.1000462. Epub 2010 Jul 19.
• [7] Loss of GTPase of immunity-associated protein 5 (Gimap5) promotes pathogenic CD4(+) T-cell development and allergic airway disease.J Allergy Clin Immunol. 2019 Jan;143(1):245-257.e6. doi: 10.1016/j.jaci.2018.10.018. Epub 2018 Oct 25.
• [8] Gimap5-dependent inactivation of GSK3 is required for CD4(+) T cell homeostasis and prevention of immune pathology.Nat Commun. 2018 Jan 30;9(1):430. doi: 10.1038/s41467-018-02897-7.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] 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.