General Information of the Ferroptosis Regulator (ID: REG10293)
Regulator Name Ubiquitin carboxyl-terminal hydrolase 7 (USP7)
Synonyms
Deubiquitinating enzyme 7; Herpesvirus-associated ubiquitin-specific protease; Ubiquitin thioesterase 7; Ubiquitin-specific-processing protease 7
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Gene Name USP7
Gene ID 7874
Regulator Type Protein coding
Uniprot ID Q93009
Sequence
MNHQQQQQQQKAGEQQLSEPEDMEMEAGDTDDPPRITQNPVINGNVALSDGHNTAEEDME
DDTSWRSEATFQFTVERFSRLSESVLSPPCFVRNLPWKIMVMPRFYPDRPHQKSVGFFLQ
CNAESDSTSWSCHAQAVLKIINYRDDEKSFSRRISHLFFHKENDWGFSNFMAWSEVTDPE
KGFIDDDKVTFEVFVQADAPHGVAWDSKKHTGYVGLKNQGATCYMNSLLQTLFFTNQLRK
AVYMMPTEGDDSSKSVPLALQRVFYELQHSDKPVGTKKLTKSFGWETLDSFMQHDVQELC
RVLLDNVENKMKGTCVEGTIPKLFRGKMVSYIQCKEVDYRSDRREDYYDIQLSIKGKKNI
FESFVDYVAVEQLDGDNKYDAGEHGLQEAEKGVKFLTLPPVLHLQLMRFMYDPQTDQNIK
INDRFEFPEQLPLDEFLQKTDPKDPANYILHAVLVHSGDNHGGHYVVYLNPKGDGKWCKF
DDDVVSRCTKEEAIEHNYGGHDDDLSVRHCTNAYMLVYIRESKLSEVLQAVTDHDIPQQL
VERLQEEKRIEAQKRKERQEAHLYMQVQIVAEDQFCGHQGNDMYDEEKVKYTVFKVLKNS
SLAEFVQSLSQTMGFPQDQIRLWPMQARSNGTKRPAMLDNEADGNKTMIELSDNENPWTI
FLETVDPELAASGATLPKFDKDHDVMLFLKMYDPKTRSLNYCGHIYTPISCKIRDLLPVM
CDRAGFIQDTSLILYEEVKPNLTERIQDYDVSLDKALDELMDGDIIVFQKDDPENDNSEL
PTAKEYFRDLYHRVDVIFCDKTIPNDPGFVVTLSNRMNYFQVAKTVAQRLNTDPMLLQFF
KSQGYRDGPGNPLRHNYEGTLRDLLQFFKPRQPKKLYYQQLKMKITDFENRRSFKCIWLN
SQFREEEITLYPDKHGCVRDLLEECKKAVELGEKASGKLRLLEIVSYKIIGVHQEDELLE
CLSPATSRTFRIEEIPLDQVDIDKENEMLVTVAHFHKEVFGTFGIPFLLRIHQGEHFREV
MKRIQSLLDIQEKEFEKFKFAIVMMGRHQYINEDEYEVNLKDFEPQPGNMSHPRPWLGLD
HFNKAPKRSRYTYLEKAIKIHN

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Family Peptidase C19 family
Function
Hydrolase that deubiquitinates target proteins such as FOXO4, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53- dependent transcription regulation, cell growth repression and apoptosis. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions. Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1- like complex; may act by deubiquitinating components of the PRC1-like complex. Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo. Exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function. Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins. Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells. Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis. Involved in the regulation of WASH-dependent actin polymerization at the surface of endosomes and the regulation of endosomal protein recycling. It maintains optimal WASH complex activity and precise F-actin levels via deubiquitination of TRIM27 and WASHC1.

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HGNC ID
HGNC:12630
KEGG ID hsa:7874
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
USP7 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Transferrin receptor protein 1 (TFRC) [Driver; Suppressor; Marker]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Ischemia/reperfusion injury ICD-11: DB98
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Male Sprague-Dawley (SD) rats (250-300 g) were purchased from the Laboratory Animal Center, Xiangya School of Medicine, Central South University, China. Briefly, a left thoracotomy was carried out in the fourth intercostal space and the heart was exposed via opening the pericardium. The left coronary artery was around via a 4-0 silk suture and a snare was formed by passing both ends of the suture via a short polyethylene tubing. Blockage of the coronary artery was conducted via clamping the snare against the heart surface. Reperfusion was performed by release of the snare. The sham group conducted the same procedure but without ischemia (the snare was not tightened). To establish the I/R injury model, the rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion.

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Response regulation A novel pathway of USP7/p53/TfR1 has been identified in the ischemia/reperfusion (I/R)-treated rat hearts, where up-regulation of USP7 promotes ferrptosis via activation of the p53/TfR1 pathway.
Heme oxygenase 1 (HMOX1) [Driver; Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Driver/Suppressor
Responsed Disease Spinal cord injury ICD-11: ND51
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
rSCs (Rat spinal cords)
In Vivo Model
Forty-eight adult female Sprague-Dawley rats weighing 200-220 g were purchased from Hunan SJA Laboratory Animal Co., Ltd. (Hunan, China) and divided into the following eight groups: sham (n = 6), SCI (n = 6), SCI + lentivirus (LV)-negative control 1 (NC1) (n = 6), SCI + LV-HMOX-1 (n = 6), SCI + LV-NC2 (n = 6), SCI + LV-USP7 (n = 6), SCI + LV-USP7 + sh-NC (n = 6), and SCI + LV-USP7 + sh-HMOX-1 (n = 6) groups. One week after animal adaptation and 30 min before operation, a subcutaneous injection of buprenorphine (0.05 mg/kg) was administered to the rats, along with inhalation of 5% isoflurane and an intraperitoneal injection of ketamine (75 mg/kg) and thiazide (10 mg/kg).

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Response regulation In spinal cord injury (SCI) rats, USP7 directly bound to HMOX-1 and its overexpression promoted HMOX-1 expression via deubiquitination. To sum up, USP7 overexpression facilitated the expression of HMOX-1 through deubiquitination, thereby reducing ferroptosis and alleviating SCI.
Ischemia/reperfusion injury [ICD-11: DB98]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Ubiquitin carboxyl-terminal hydrolase 7 (USP7) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Male Sprague-Dawley (SD) rats (250-300 g) were purchased from the Laboratory Animal Center, Xiangya School of Medicine, Central South University, China. Briefly, a left thoracotomy was carried out in the fourth intercostal space and the heart was exposed via opening the pericardium. The left coronary artery was around via a 4-0 silk suture and a snare was formed by passing both ends of the suture via a short polyethylene tubing. Blockage of the coronary artery was conducted via clamping the snare against the heart surface. Reperfusion was performed by release of the snare. The sham group conducted the same procedure but without ischemia (the snare was not tightened). To establish the I/R injury model, the rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion.

    Click to Show/Hide
Response regulation A novel pathway of USP7/p53/TfR1 has been identified in the ischemia/reperfusion (I/R)-treated rat hearts, where up-regulation of USP7 promotes ferrptosis via activation of the p53/TfR1 pathway.
Spinal cord injury [ICD-11: ND51]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator Ubiquitin carboxyl-terminal hydrolase 7 (USP7) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model
rSCs (Rat spinal cords)
In Vivo Model
Forty-eight adult female Sprague-Dawley rats weighing 200-220 g were purchased from Hunan SJA Laboratory Animal Co., Ltd. (Hunan, China) and divided into the following eight groups: sham (n = 6), SCI (n = 6), SCI + lentivirus (LV)-negative control 1 (NC1) (n = 6), SCI + LV-HMOX-1 (n = 6), SCI + LV-NC2 (n = 6), SCI + LV-USP7 (n = 6), SCI + LV-USP7 + sh-NC (n = 6), and SCI + LV-USP7 + sh-HMOX-1 (n = 6) groups. One week after animal adaptation and 30 min before operation, a subcutaneous injection of buprenorphine (0.05 mg/kg) was administered to the rats, along with inhalation of 5% isoflurane and an intraperitoneal injection of ketamine (75 mg/kg) and thiazide (10 mg/kg).

    Click to Show/Hide
Response regulation In spinal cord injury (SCI) rats, USP7 directly bound to HMOX-1 and its overexpression promoted HMOX-1 expression via deubiquitination. To sum up, USP7 overexpression facilitated the expression of HMOX-1 through deubiquitination, thereby reducing ferroptosis and alleviating SCI.
References
Ref 1 Ubiquitin-specific protease 7 promotes ferroptosis via activation of the p53/TfR1 pathway in the rat hearts after ischemia/reperfusion. Free Radic Biol Med. 2021 Jan;162:339-352. doi: 10.1016/j.freeradbiomed.2020.10.307. Epub 2020 Nov 4.
Ref 2 USP7 regulates HMOX-1 via deubiquitination to suppress ferroptosis and ameliorate spinal cord injury in rats. Neurochem Int. 2023 Sep;168:105554. doi: 10.1016/j.neuint.2023.105554. Epub 2023 May 29.