Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXSTB64)

• DOT Name: DAP3-binding cell death enhancer 1 (DELE1)
• Synonyms: DAP3-binding cell death enhancer 1, long form; DELE1(L); Death ligand signal enhancer
• Gene Name: DELE1
• Related Disease: Cystic fibrosis
• UniProt ID: DELE1_HUMAN
• PDB ID: 8D9X
• Pfam ID: PF08238
• Sequence:
  MWRLPGLLGRALPRTLGPSLWRVTPKSTSPDGPQTTSSTLLVPVPNLDRSGPHGPGTSGG
  PRSHGWKDAFQWMSSRVSPNTLWDAISWGTLAVLALQLARQIHFQASLPAGPQRVEHCSW
  HSPLDRFFSSPLWHPCSSLRQHILPSPDGPAPRHTGLREPRLGQEEASAQPRNFSHNSLR
  GARPQDPSEEGPGDFGFLHASSSIESEAKPAQPQPTGEKEQDKSKTLSLEEAVTSIQQLF
  QLSVSIAFNFLGTENMKSGDHTAAFSYFQKAAARGYSKAQYNAGLCHEHGRGTPRDISKA
  VLYYQLAASQGHSLAQYRYARCLLRDPASSWNPERQRAVSLLKQAADSGLREAQAFLGVL
  FTKEPYLDEQRAVKYLWLAANNGDSQSRYHLGICYEKGLGVQRNLGEALRCYQQSAALGN
  EAAQERLRALFSMGAAAPGPSDLTVTGLKSFSSPSLCSLNTLLAGTSRLPHASSTGNLGL
  LCRSGHLGASLEASSRAIPPHPYPLERSVVRLGFG
• Function: Protein kinase activator that acts as a key activator of the integrated stress response (ISR) following various stresses, such as iron deficiency and mitochondrial stress. Detects impaired protein import and processing in mitochondria, activating the ISR. May also required for the induction of death receptor-mediated apoptosis through the regulation of caspase activation ; [DAP3-binding cell death enhancer 1]: Protein kinase activator that activates the ISR in response to iron deficiency: iron deficiency impairs mitochondrial import, promoting DELE1 localization at the mitochondrial surface, where it binds and activates EIF2AK1/HRI to trigger the ISR; [DAP3-binding cell death enhancer 1 short form]: Protein kinase activator generated by protein cleavage in response to mitochondrial stress, which accumulates in the cytosol and specifically binds to and activates the protein kinase activity of EIF2AK1/HRI. It thereby activates the integrated stress response (ISR): EIF2AK1/HRI activation promotes eIF-2-alpha (EIF2S1) phosphorylation, leading to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, the master transcriptional regulator of the ISR.
• Tissue Specificity: Detected in liver, skeletal muscle, kidney, pancreas, spleen, thyroid, testis, ovary, small intestine and colon.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[1]

3 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 DAP3-binding cell death enhancer 1 (DELE1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DAP3-binding cell death enhancer 1 (DELE1).	[3]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of DAP3-binding cell death enhancer 1 (DELE1).	[4]

References

• [1] Epidemiology and a novel procedure for large scale analysis of CFTR rearrangements in classic and atypical CF patients: a multicentric Italian study.J Cyst Fibros. 2008 Sep;7(5):347-51. doi: 10.1016/j.jcf.2007.12.004. Epub 2008 Feb 14.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.