Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY5YQFX)

• DOT Name: Tripartite motif-containing protein 55 (TRIM55)
• Synonyms: EC 2.3.2.27; Muscle-specific RING finger protein 2; MuRF-2; MuRF2; RING finger protein 29
• Gene Name: TRIM55
• Related Disease:
  Congestive heart failure
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
• UniProt ID: TRI55_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00643 ; PF13445
• Sequence:
  MSASLNYKSFSKEQQTMDNLEKQLICPICLEMFTKPVVILPCQHNLCRKCASDIFQASNP
  YLPTRGGTTMASGGRFRCPSCRHEVVLDRHGVYGLQRNLLVENIIDIYKQESTRPEKKSD
  QPMCEEHEEERINIYCLNCEVPTCSLCKVFGAHKDCQVAPLTHVFQRQKSELSDGIAILV
  GSNDRVQGVISQLEDTCKTIEECCRKQKQELCEKFDYLYGILEERKNEMTQVITRTQEEK
  LEHVRALIKKYSDHLENVSKLVESGIQFMDEPEMAVFLQNAKTLLKKISEASKAFQMEKI
  EHGYENMNHFTVNLNREEKIIREIDFYREDEDEEEEEGGEGEKEGEGEVGGEAVEVEEVE
  NVQTEFPGEDENPEKASELSQVELQAAPGALPVSSPEPPPALPPAADAPVTQGEVVPTGS
  EQTTESETPVPAAAETADPLFYPSWYKGQTRKATTNPPCTPGSEGLGQIGPPGSEDSNVR
  KAEVAAAAASERAAVSGKETSAPAATSQIGFEAPPLQGQAAAPASGSGADSEPARHIFSF
  SWLNSLNE
• Function: E3 ubiquitin ligase that plays an important role in regulating cardiac development and contractility, muscle growth, metabolism, and fiber-type differentiation. Acts as a critical factor that regulates cardiomyocyte size during development in concert with TRIM63 by regulating E2F1-mediated gene expression. Plays a role in apoptosis induction in cardiomyocytes by promoting ubiquitination of the DUSP1 phosphatase. Promotes non-canonical NF-kappa-B signaling and B-cell-mediated immune responses by mediating NFKB2 'Lys-48'-linked ubiquitination and processing. In turn, NFKB2 is further processed by valosin-containing protein/VCP, an ATPase that mediates ubiquitin-dependent protein degradation by the proteasome. May play a role in preventing macrophages from producing inflammatory factors and migrating by downregulating the level of nuclear NF-kappa-B subunit RELA. Modifies also PPARG via polyubiquitination and accelerates PPARG proteasomal degradation to inhibit its activity.
• Tissue Specificity: Highly expressed in muscle. Low-level expression in liver.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Hepatitis	DISXXX35	Strong	Altered Expression	[2]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tripartite motif-containing protein 55 (TRIM55).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tripartite motif-containing protein 55 (TRIM55).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tripartite motif-containing protein 55 (TRIM55).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Tripartite motif-containing protein 55 (TRIM55).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tripartite motif-containing protein 55 (TRIM55).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tripartite motif-containing protein 55 (TRIM55).	[10]

References

• [1] Small-molecule-mediated chemical knock-down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure.J Cachexia Sarcopenia Muscle. 2019 Oct;10(5):1102-1115. doi: 10.1002/jcsm.12448. Epub 2019 May 29.
• [2] The E3 ubiquitin ligase MuRF2 attenuates LPS-induced macrophage activation by inhibiting production of inflammatory cytokines and migration.FEBS Open Bio. 2018 Jan 8;8(2):234-243. doi: 10.1002/2211-5463.12367. eCollection 2018 Feb.
• [3] Overexpression of Tripartite Motif Conaining 55 (TRIM55) Inhibits Migration and Invasion of Hepatocellular Carcinoma (HCC) Cells via Epithelial-Mesenchymal Transition and Matrix Metalloproteinase-2 (MMP2).Med Sci Monit. 2019 Jan 27;25:771-777. doi: 10.12659/MSM.910984.
• [4] Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy.Int J Mol Sci. 2014 May 26;15(6):9302-13. doi: 10.3390/ijms15069302.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.