Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene. [5] [6] [7] [8]
Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene. [5] [6] [7] [8]
USP7 or HAUSP is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates. [9] Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP activity generally stabilizes its substrate proteins.
HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53. [10] Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress.
Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.
USP7 can deubiquitinate histone H2B and this activity is associated with gene silencing in Drosophila. [11] USP7 associates with a metabolic enzyme, GMP synthetase (GMPS) and this association stimulates USP7 deubiquitinase activity towards H2B. [11] The USP7-GMPS complex is recruited to the polycomb (Pc) region in Drosophila and contributes to epigenetic silencing of homeotic genes. [12]
USP7 was originally identified as a protein associated with the ICP0 protein of herpes simplex virus (HSV), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0.
More recently, an interaction between USP7 and the EBNA1 protein of Epstein–Barr virus (EBV) (another herpesvirus) was also discovered. [13] This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV. Additionally, human USP7 was also shown to form a complex with GMPS and this complex is recruited to EBV genome sequences. [14] USP7 was shown to be important for histone H2B deubiquitination in human cells and for deubiquitination of histone H2B incorporated in the EBV genome. Thus USP7 may also be important for regulation of viral gene expression.
The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes.
The following is a list of some of the known cellular binding partners of USP7/HAUSP:
USP7 has been shown to interact with Ataxin 1, [17] CLSPN [18] and P53. [10] A proteomic screen conducted to identify interacting partners of 75 human deubiquitinating enzymes (DUBs) has revealed several novel binding partners of USP7. [19]
Loss-of-function mutations of USP7 are associated with neurodevelopmental disorder whose symptoms include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal, [20] [21]
USP7 can be used as a senolytic agent due to ubiquitination and subsequent proteasome degradation of mdm2, thereby increasing p53 activity. [15]
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.
USP26 is a peptidase enzyme. The USP26 gene is an X-linked gene exclusively expressed in the testis and it codes for the ubiquitin-specific protease 26. The USP26 gene is found at Xq26.2 on the X-chromosome as a single exon. The enzyme that this gene encodes comprises 913 amino acid residues and it is 104 kilodalton in size, which is transcribed from a sequence of 2794 nucleotide base-pairs on the X-chromosome. The USP26 enzyme is a deubiquitinating enzyme that places a very significant role in the regulation of protein turnover during spermatogenesis. It is a testis-specific enzyme that is solely express in spermatogonia and can prevent the degradation of ubiquitinated USP26 substrates.
Probable ubiquitin carboxyl-terminal hydrolase FAF-X is an enzyme that in humans is encoded by the USP9X gene.
Ubiquitin carboxyl-terminal hydrolase 8 is an enzyme that in humans is encoded by the USP8 gene.
Ubiquitin specific peptidase 10, also known as USP10, is an enzyme which in humans is encoded by the USP10 gene.
Ubiquitin carboxyl-terminal hydrolase 16 is an enzyme that in humans is encoded by the USP16 gene.
Ubiquitin specific protease 4 (USP4) is an enzyme that cleaves ubiquitin from a number of protein substrates. Prior to the standardization of nomenclature USP4 was known as UNP, and was one of the first deubiquitinating enzymes to be identified in mammals. In the mouse and human the USP4 protein is encoded by a gene containing 22 exons.
Ubiquitin carboxyl-terminal hydrolase or Ubiquitin specific protease 11 is an enzyme that in humans is encoded by the USP11 gene. USP11 belongs to the Ubiquitin specific proteases family (USPs) which is a sub-family of the Deubiquitinating enzymes (DUBs).USPs are multiple domain proteases and belong to the C19 cysteine proteases sub‒family. Depending on their domain architecture and position there is different homology between the various members. Generally the largest domain is the catalytic domain which harbours the three residue catalytic triad that is included inside conserved motifs. The catalytic domain also contains sequences that are not related with the catalysis function and their role is mostly not clearly understood at present, the length of these sequences varies for each USP and therefore the length of the whole catalytic domain can range from approximately 295 to 850 amino acids. Particular sequences inside the catalytic domain or at the N‒terminus of some USPs have been characterised as UBL and DUSP domains respectively. In some cases, regarding the UBL domains, it has been reported to have a catalysis enhancing function as in the case of USP7. In addition, a so‒called DU domain module is the combination of a DUSP domain followed by a UBL domain separated by a linker and is found in USP11 as well as in USP15 and USP4.
Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a type I interferon receptor repressor and an isopeptidase. In humans, it is encoded by the USP18 gene. USP18 is induced by the immune response to type I and III interferons, and serves as a negative regulator of type I interferon, but not type III interferon. Loss of USP18 results in increased responsiveness to type I interferons and life-threatening autoinflammatory disease in humans due to the negative regulatory function of USP18 in interferon signal transduction. Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove ISG15 conjugates from a broad range of protein substrates, a process known as deISGylation.
Ubiquitin-specific protease 36 is an enzyme that in humans is encoded by the USP36 gene.
Ubiquitin carboxyl-terminal hydrolase 1 is an enzyme that in humans is encoded by the USP1 gene.
Ubiquitin carboxyl-terminal hydrolase 15 is an enzyme that in humans is encoded by the USP15 gene.
E3 ubiquitin-protein ligase NRDP1 is an enzyme that in humans is encoded by the RNF41 gene.
Ubiquitin carboxyl-terminal hydrolase 48 is an enzyme that in humans is encoded by the USP48 gene.
Ubiquitin carboxyl-terminal hydrolase 2 is an enzyme that in humans is encoded by the USP2 gene.
Ubiquitin-specific protease 14 is an enzyme that in humans is encoded by the USP14 gene.
Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.
Ubiquitin specific peptidase 22 is a protein that in humans is encoded by the USP22 gene on chromosome 17. USP22 is known to function as a histone deubiquitinating component of the transcription regulatory histone acetylation (HAT) complex SAGA.
Ubiquitin specific peptidase 25 is a protein that in humans is encoded by the USP25 gene.
The ubiquitin carboxyl-terminal hydrolase 27, also known as deubiquitinating enzyme 27, ubiquitin thioesterase 27 and USP27X, is a deubiquitinating enzyme which is mainly characterized for cleaving ubiquitin (Ub) from proteins and other molecules. Ubiquitin binds to proteins so as to regulate the degradation of them via the proteasome and lysosome among many other functions.
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