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Deubiquitinating Enzymes (DUBs)

Introduction of deubiquitinating enzymes

The ubiquitin-proteasome pathway is an important protein degradation regulatory system in cells. Through the ubiquitination of substrate proteins and proteasomal degradation, a variety of cellular activities can be affected or regulated, including: gene transcription, cell cycle regulation, immune response, cell receptor function, tumor growth, and inflammatory processes. Due to the extensive and reversible function of this pathway, it is strictly regulated in the body, and the regulation of deubiquitinating enzyme is an important link. At present, it is confirmed that there are many deubiquitinating enzymes in the cells, which are mainly divided into five types, which are mainly ubiquitin carboxy terminal hydrolase family and ubiquitin-specific processing enzyme family. These different types of deubiquitinating enzymes are capable of hydrolyzing the linkages between the ubiquitin chains on the substrate proteins, deubiquitinating, and inversely regulating protein degradation, thereby affecting protein function.

Classification of deubiquitinating enzymes

Deubiquitinating enzymes are a large family of proteases. It mainly hydrolyzes ubiquitin molecules from ubiquitin-linked proteins or precursor proteins by hydrolyzing ester bonds, peptide bonds or isopeptide bonds at the carboxy terminus of ubiquitin. A variety of deubiquitinating enzymes have been isolated and identified from yeast and humans. Based on the structural similarity (ie, amino acid sequence homology) of these deubiquitinating enzymes and possible mechanisms of action, the current deubiquitinating enzymes can mainly divide into five types, which are mainly ubiquitin carboxy terminal hydrolase family and ubiquitin-specific processing enzyme family.

Ubiquitin carboxy terminal hydrolase family (UCHs)

UCHs belong to cysteine proteases. These proteins are usually small molecule proteins, such as UCHL21, 22, 23, 24, 25. Their substrates are usually also small molecular weight polypeptides. UCHs can release ubiquitin molecules from small polypeptide substrates by cleaving the 76 glycine at the C-terminus. The narrowing of the gaps in the active sites of UCHs and the limitation of the diameter of the circular structure play important roles in specifically recognizing the substrate in a certain extent by preventing its binding and catalysis of some macromolecular ubiquitinated proteins.

Ubiquitin-specific processing enzyme family (UBPs or USPs)

This family is currently the most widely known member of the deubiquitinating enzyme, and the most diverse structure, is also a cysteine protease, including Ubp2M, UBP41, UBP4, HAUSP, ISOT1 and so on. These enzyme molecules contain two short and conserved fragments, the lysine cassette and the histidine cassette, which have catalytic three-link residues (cysteine, histidine and aspartic acid/asparagine), which can remove ubiquitin molecules from large proteins.

Ovarian tumor associated protease (OTU)

Through crystal structure analysis, it was found that although the protease is different in amino acid sequence from other deubiquitinating enzymes, it also has a core domain consisting of a triple catalytic active site (Cys, His, Asp), which is very similar to the UBP family of proteins and proven to be deubiquitinating.


This type of deubiquitinating enzyme is currently only a member of Ataxin23. Ataxin23 contains a domain called Josephin, which contains an amino acid sequence with a cysteine cassette and a histidine cassette of UCHs and has similarities with USPs. MPN/JAMM protease

This class of deubiquitinating enzymes, POH1, is a homologue in yeast cells called Rpn 11. This is a class of metalloproteinases that bind to ubiquitin molecules on ubiquitinated proteins, with MPN sequences and JAMM (Jab/MPN domain-associated metalloopeptidase) sequences. This sequence contains two conserved two histidine residues and one aspartic acid residue, which together with the divalent zinc ions constitute a catalytic center.

Deubiquitinating enzymes and diseases

Deubiquitinating enzyme and neuropathy

Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative diseases, which are characterized by axonal degeneration of neurons and formation of elliptic inclusion bodies at the nerve endings and aggregation of β2 amyloid (Aβ) form age spots and neurofibrillary tangles (NFT). In 1998, Leroy et al found a missense point mutation in the UCH2L1 gene in a family of German familial Parkinson's disease, which replaced the 39th amino acid Ile with Met, resulting in the partial loss of the catalytic activity of this thiol protease. Therefore, the mutation induces the pathological changes such as disorders of proteolytic pathways and protein aggregation in neurons. The presence of UCH2L1 in Leroy bodies and its relationship to the proteolytic substrate pathway of the ubiquitin-proteasome pathway is preliminarily revealed to be related to the pathogenesis of PD. In recent years, with the development of molecular genetics, it has been determined that the UCH2L1 gene mutation is one of the causative genes of autosomal dominant Parkinson's disease. In 2002, Liu et al. found that the UCH2L1 gene encodes two oppositely acting enzyme activities, one is the recognized activity of ubiquitin carboxy terminal hydrolase, and the other is ubiquitin ligand activity. The specific physiological function of this activity is not yet clear. Some scholars have hypothesized that this ligand activity is related to the S18Y locus polymorphism of UCH2L1 and depends on the form of UCH2L1 dimer, which is unique in the UCHs family, which may be depleted free ubiquitin by binding to ubiquitin. The process thereby hinder the degradation of substrate proteins dependent on the ubiquitin pathway, cause accumulation of β2 amyloid in Leroy bodies, such as α2 synuclein and senile plaques, leading to pathological changes such as PD and AD. In addition, the accumulation of amyloid precursor protein (APP) and the decreased level of functional UCH2L1 in the brain of AD patients, and the exogenous injection of UCH2L1 can eliminate these abnormal proteins. These all indicate that UCH2L1 has a very close relationship with the pathogenesis of neurodegenerative diseases.

Deubiquitinating enzyme and tumor growth

The role of deubiquitinating enzymes in tumor growth has been multifaceted. Many literatures have reported the expression of UCHL21 protein in tumor cells: such as lung cancer, ovarian cancer, colon cancer, etc., and the level of UCHL21 is closed with tumor invasion and prognosis. The molecular mechanism is still being further studied. Based on the results of previous studies, it is speculated that the regulation of the cell cycle may lead to abnormal proliferation of tumor cells. Deubiquitinating enzymes may also regulate cell proliferation and differentiation and inhibit the growth of tumor cells. The tumor suppressor gene p53 is a typical example. In the intracellular, p53 is ubiquitinated by the action of a ubiquitin ligase, Mdm2, to enter the proteasome degradation. In recent years, experiments have confirmed that there is a deubiquitinating enzyme in the cell, HAUSP, which can deubiquitinate p53 both in vivo and in vitro. With the deepening of research, Muyang et al. (2002) reported that HAUSP (USP7) specifically binds to the p53 ubiquitination chain, deubiquitinating, reducing p53 degradation, enhancing stability, and inhibiting tumor cell growth. This can be involved in the regulation of p53-mediated gene regulation by affecting the stability of p53. These experimental results have proposed new therapeutic targets for tumor research.


  1. Johnston S C, et al. Structural basis for the specificity of ubiquitin C-terminal hydrolases. EMBO J. 2000, 18(14): 3877-3887.
  2. Evans P C, et al. A novel type of deubiquitinating enzyme. J Biol Chem. 2003, 278(25): 23180-23186.
  3. Liu Y, et al. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinsons disease susceptibility.Cell. 2002, 111(2): 209-218.
  4. Meulmeester E, et al. ATM-mediated phosphorylations inhibit Madm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle.2005, 4(9): 1166-1170.

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