Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8XE247)

• DOT Name: Lysosomal enzyme trafficking factor (LYSET)
• Synonyms: GNPTAB cleavage and activity factor; GCAF; Transmembrane protein 251
• Gene Name: LYSET
• Related Disease: Dysostosis multiplex, Ain-Naz type
• UniProt ID: LYSET_HUMAN
• Pfam ID: PF15190
• Sequence:
  MPKPPDYSELSDSLTLAVGTGRFSGPLHRAWRMMNFRQRMGWIGVGLYLLASAAAFYYVF
  EISETYNRLALEHIQQHPEEPLEGTTWTHSLKAQLLSLPFWVWTVIFLVPYLQMFLFLYS
  CTRADPKTVGYCIIPICLAVICNRHQAFVKASNQISRLQLIDT
• Function: Required for mannose-6-phosphate-dependent trafficking of lysosomal enzymes. LYSET bridges GlcNAc-1-phosphate transferase (GNPTAB), to the membrane-bound transcription factor site-1 protease (MBTPS1), thus allowing proteolytic activation of the GNPTAB. GNPTAB is involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes. LYSET is thus an essential factor for maturation and delivery of lysosomal hydrolases ; (Microbial infection) Essential for infection by muliple viruses, including SARS-CoV-2, that utilize activated cathepsins for entry after M6P-dependent lysosomal transport.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dysostosis multiplex, Ain-Naz type	DISSD5BQ	Limited	Autosomal recessive	[1]

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 Lysosomal enzyme trafficking factor (LYSET).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lysosomal enzyme trafficking factor (LYSET).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysosomal enzyme trafficking factor (LYSET).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysosomal enzyme trafficking factor (LYSET).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Lysosomal enzyme trafficking factor (LYSET).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysosomal enzyme trafficking factor (LYSET).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Lysosomal enzyme trafficking factor (LYSET).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lysosomal enzyme trafficking factor (LYSET).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysosomal enzyme trafficking factor (LYSET).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysosomal enzyme trafficking factor (LYSET).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Lysosomal enzyme trafficking factor (LYSET).	[12]

References

• [1] Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature. Hum Mutat. 2021 Jan;42(1):89-101. doi: 10.1002/humu.24139. Epub 2020 Nov 30.
• [2] 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.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.