Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEE02J4)

• DOT Name: Ubiquitin thioesterase otulin (OTULIN)
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme otulin; OTU domain-containing deubiquitinase with linear linkage specificity; Ubiquitin thioesterase Gumby
• Gene Name: OTULIN
• Related Disease:
  Infantile-onset periodic fever-panniculitis-dermatosis syndrome
  Advanced cancer
  Autoimmune disease
  Autoinflammatory syndrome
  Cerebral infarction
  Ankylosing spondylitis
• UniProt ID: OTUL_HUMAN
• PDB ID: 3ZNV; 3ZNX; 3ZNZ; 4KSJ; 4KSK; 4KSL; 4OYK; 4P0B; 5OE7; 6I9C; 6SAK
• EC Number: 3.4.19.12
• Pfam ID: PF16218
• Sequence:
  MSRGTMPQPEAWPGASCAETPAREAAATARDGGKAAASGQPRPEMQCPAEHEEDMYRAAD
  EIEKEKELLIHERGASEPRLSVAPEMDIMDYCKKEWRGNTQKATCMKMGYEEVSQKFTSI
  RRVRGDNYCALRATLFQAMSQAVGLPPWLQDPELMLLPEKLISKYNWIKQWKLGLKFDGK
  NEDLVDKIKESLTLLRKKWAGLAEMRTAEARQIACDELFTNEAEEYSLYEAVKFLMLNRA
  IELYNDKEKGKEVPFFSVLLFARDTSNDPGQLLRNHLNQVGHTGGLEQVEMFLLAYAVRH
  TIQVYRLSKYNTEEFITVYPTDPPKDWPVVTLIAEDDRHYNIPVRVCEETSL
• Function: Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response. Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex. Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex. OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex. Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis. In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation. Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent pro-inflammatory signaling.
• Reactome Pathway:
  Synthesis of active ubiquitin (R-HSA-8866652)
  Regulation of TNFR1 signaling (R-HSA-5357905)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile-onset periodic fever-panniculitis-dermatosis syndrome	DISNBL1M	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[2]
Autoinflammatory syndrome	DISCMCGL	Strong	Genetic Variation	[3]
Cerebral infarction	DISR1WNP	Strong	Altered Expression	[4]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[5]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ubiquitin thioesterase otulin (OTULIN).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Ubiquitin thioesterase otulin (OTULIN).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ubiquitin thioesterase otulin (OTULIN).	[8]

References

• [1] OTULIN deficiency causes auto-inflammatory syndrome. Cell Res. 2016 Nov;26(11):1176-1177. doi: 10.1038/cr.2016.113. Epub 2016 Sep 30.
• [2] CYLD, A20 and OTULIN deubiquitinases in NF-B signaling and cell death: so similar, yet so different.Cell Death Differ. 2017 Jul;24(7):1172-1183. doi: 10.1038/cdd.2017.46. Epub 2017 Mar 31.
• [3] An Update on Autoinflammatory Diseases: Relopathies.Curr Rheumatol Rep. 2018 May 30;20(7):39. doi: 10.1007/s11926-018-0749-x.
• [4] Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-B signaling pathway in cerebral ischemia/reperfusion rats.J Neuroinflammation. 2018 Mar 15;15(1):83. doi: 10.1186/s12974-018-1117-5.
• [5] Genetic loci that regulate ectopic calcification in response to knee trauma in LG/J by SM/J advanced intercross mice.J Orthop Res. 2015 Oct;33(10):1412-23. doi: 10.1002/jor.22944. Epub 2015 Jun 19.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.