Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA4UJCF)

• DOT Name: E3 ubiquitin-protein ligase TRIM21 (TRIM21)
• Synonyms: EC 2.3.2.27; 52 kDa Ro protein; 52 kDa ribonucleoprotein autoantigen Ro/SS-A; RING finger protein 81; Ro(SS-A); Sjoegren syndrome type A antigen; SS-A; Tripartite motif-containing protein 21
• Gene Name: TRIM21
• Related Disease:
  Colon cancer
  Gastroesophageal reflux disease
  Acromegaly
  Adenoma
  Atrioventricular block
  Breast carcinoma
  Cardiovascular disease
  Colon carcinoma
  Colorectal adenoma
  Dermatomyositis
  Familial Mediterranean fever
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Idiopathic inflammatory myopathy
  Keratoconjunctivitis sicca
  Lung cancer
  Lung carcinoma
  Myositis disease
  Neoplasm
  Neuroendocrine neoplasm
  Psoriasis
  Skin disease
  Squamous cell carcinoma
  Stroke
  Systemic sclerosis
  Trichohepatoenteric syndrome
  Type-1/2 diabetes
  Nasopharyngeal carcinoma
  Pancreatic cancer
  Subacute cutaneous lupus erythematosus
  Glomerulonephritis
  Arthritis
  Barrett esophagus
  Breast cancer
  Cutaneous lupus erythematosus
  Familial adenomatous polyposis
  Leukoencephalopathy with vanishing white matter
  Lupus
  Lupus nephritis
  Polyp
  Rheumatoid arthritis
• UniProt ID: RO52_HUMAN
• PDB ID: 2IWG; 5JPX; 5OLM; 6FGA; 6S53; 7BBD; 8A58
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF00097
• Sequence:
  MASAARLTMMWEEVTCPICLDPFVEPVSIECGHSFCQECISQVGKGGGSVCPVCRQRFLL
  KNLRPNRQLANMVNNLKEISQEAREGTQGERCAVHGERLHLFCEKDGKALCWVCAQSRKH
  RDHAMVPLEEAAQEYQEKLQVALGELRRKQELAEKLEVEIAIKRADWKKTVETQKSRIHA
  EFVQQKNFLVEEEQRQLQELEKDEREQLRILGEKEAKLAQQSQALQELISELDRRCHSSA
  LELLQEVIIVLERSESWNLKDLDITSPELRSVCHVPGLKKMLRTCAVHITLDPDTANPWL
  ILSEDRRQVRLGDTQQSIPGNEERFDSYPMVLGAQHFHSGKHYWEVDVTGKEAWDLGVCR
  DSVRRKGHFLLSSKSGFWTIWLWNKQKYEAGTYPQTPLHLQVPPCQVGIFLDYEAGMVSF
  YNITDHGSLIYSFSECAFTGPLRPFFSPGFNDGGKNTAPLTLCPLNIGSQGSTDY
• Function: E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B ('Thr-187' phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by catalyzing polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Regulates also autophagy through FIP200/RB1CC1 ubiquitination and subsequent decreased protein stability. Represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through 'Lys-63'-linked ubiquitination of NMI. During viral infection, promotes cell pyroptosis by mediating 'Lys-6'-linked ubiquitination of ISG12a/IFI27, facilitating its translocation into the mitochondria and subsequent CASP3 activation. When up-regulated through the IFN/JAK/STAT signaling pathway, promotes 'Lys-27'-linked ubiquitination of MAVS, leading to the recruitment of TBK1 and up-regulation of innate immunity. Mediates 'Lys-63'-linked polyubiquitination of G3BP1 in response to heat shock, leading to stress granule disassembly.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed in fetal and adult heart and fetal lung.
• KEGG Pathway: Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)
  Interferon gamma signaling (R-HSA-877300)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Antigen processing (R-HSA-983168)
  STING mediated induction of host immune responses (R-HSA-1834941)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Definitive	Altered Expression	[1]
Gastroesophageal reflux disease	DISQ8G5S	Definitive	Biomarker	[2]
Acromegaly	DISCC73U	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Atrioventricular block	DIS8YLE6	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[9]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[10]
Familial Mediterranean fever	DISVP5WP	Strong	Biomarker	[11]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Altered Expression	[14]
Keratoconjunctivitis sicca	DISNOENH	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Myositis disease	DISCIXF0	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[6]
Neuroendocrine neoplasm	DISNPLOO	Strong	Biomarker	[18]
Psoriasis	DIS59VMN	Strong	Biomarker	[19]
Skin disease	DISDW8R6	Strong	Altered Expression	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[21]
Stroke	DISX6UHX	Strong	Biomarker	[22]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[23]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[24]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[25]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[26]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[27]
Subacute cutaneous lupus erythematosus	DIS6XDK0	moderate	Biomarker	[28]
Glomerulonephritis	DISPZIQ3	Disputed	Biomarker	[29]
Arthritis	DIST1YEL	Limited	Biomarker	[30]
Barrett esophagus	DIS416Y7	Limited	Altered Expression	[31]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[6]
Cutaneous lupus erythematosus	DISOIX6L	Limited	Biomarker	[31]
Familial adenomatous polyposis	DISW53RE	Limited	Biomarker	[32]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Limited	Altered Expression	[31]
Lupus	DISOKJWA	Limited	Biomarker	[33]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[34]
Polyp	DISRSLYF	Limited	Biomarker	[35]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[36]

13 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 E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[40]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[41]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[42]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[43]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[44]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[45]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[46]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[47]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[48]
eucalyptol	DME5CK3	Investigative	eucalyptol decreases the expression of E3 ubiquitin-protein ligase TRIM21 (TRIM21).	[49]

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