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Monoubiquitin Signaling in Genetic Diseases
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Ubiquitination is a reversible post-translational modification that controls protein function and stability. Different types of ubiquitination were described including polyubiquitination, the attachment of multiple ubiquitin residues, or monoubiquitination, the attachment of a single ubiquitin molecule. While most of the studies have described the role of polyubiquitination, recent evidences show that monoubiquitination is a key regulator of different cellular processes, including vesicular trafficking and protein complex formation and degradation. Enzymes regulating monoubiquitination such as E2 conjugating enzymes, E3 ligases or ubiquitin hydrolases, are found altered in several genetic diseases, including Parkinson's disease or Noonan syndrome.

ubiquitin system genetic diseases ubiquitin ligase deubiquitinases monoubiquitin signaling vesicular trafficking protein complex formation
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1. Introduction

Ubiquitination is a reversible post-translational modification process during which the highly conserved 76-aminoacid protein ubiquitin is conjugated to target proteins. Ubiquitin can be conjugated to a protein substrate via distinct mechanisms. Monoubiquitination is the attachment of a single ubiquitin molecule to a single lysine residue on a substrate protein, whereas multi-monoubiquitination is the conjugation of a single ubiquitin molecule to multiple lysine residues. Polyubiquitination occurs when ubiquitin molecules are attached end-to-end to a lysine residue on a substrate protein to form a poly-ubiquitin chain. In this case, ubiquitin molecules are conjugated through one of the seven lysine residues present on the ubiquitin itself (K6, K11, K27, K29, K33, K48, and 63) or the N-terminal methionine (M1). While most of the studies have described the role of specific polyubiquitination, such as K48-linked polyubiquitination for proteasomal degradation [1][2] or K63-linked polyubiquitination for vesicular trafficking [3], emerging evidences implicate monoubiquitination and multi-monoubiquitination in controlling numerous aspects of protein function, such as degradation, subcellular localization, and protein–protein interaction. In this review, we focus on the role of monoubiquitin conjugation in normal physiology and genetic disease.

Comparing to the role of polyubiquitination in proteasomal degradation, the function of non-degradative monoubiquitination in human disease has been relatively understudied so far. Recent emerging evidences have highlighted the key function of monoubiquitination in a wide range of cellular processes. The findings listed here only represent the most characterized enzymes controlling monoubiquitination. Nonetheless, it reflects the high prevalence of alterations of the monoubiquitin pathway in such a broad array of genetic disorders. This suggests that disruption of the monoubiquitin pathway may be a major force driving the pathogenic phenotypes of such diseases.

Table 1. Genetic diseases associated with genes regulating monoubiquitination. Short list of substrates modified by the indicated E2 conjugating enzymes, E3 ligases, and ubiquitin hydrolases (DUBs) are shown, together with the indication of the modulated cellular functions and the type of mutations detected in patients.

Disease Gene Type of Enzyme Monoubiquitinated Substrate Cellular Function Disease-Associated Mutations
X-linked syndromic mental retardation UBE2A Ubiquitin-conjugating enzyme E2 A PCNA [4]; Histone H2B [5] DNA damage tolerance pathway [6][7][8]; epigenetic regulation [5] Loss of function: missense mutations, microdeletions, larger deletions [9][10]
Autosomal recessive juvenile parkinsonism Parkin or PARK2 RBR E3 ubiquitin ligase VDAC1 [11][12] Mitophagy, apoptosis [13][14] Loss of function: missense mutations, deletions [15]
Fanconi Anemia UBE2T Ubiquitin-conjugating enzyme E2 T FANCD2/FANCI [16][17] Cross-linked DNA repair [18][19] Loss of function: missense mutations [20]
FANCL PHD FINGER E3 ubiquitin ligase Loss of function: missense, frameshift mutations [21]
BRCA1 RING E3 ubiquitin ligase FANCD2/FANCI [22] Loss of function: missense frameshift mutations, deletions [23]
Charcot-Marie-Tooth disease LRSAM1 RING E3 ubiquitin ligase TSG101 [24] Endosomal sorting [25] Loss of function: missense, frameshift mutations [26]
Cushing disease USP8 Ubiquitin specific peptidase 8 EGFR [27][28]; CHMP1B [29] Endosomal sorting [30][31] Gain of function: missense mutations [32][33]
Noonan Syndrome LZTR1 BTB-Kelch ubiquitin ligase adaptor RAS [34][35]; CHMP1B [36] RAS localization and signaling [34][35]; VEGFR trafficking and signaling [36] Loss of function: missense, frameshift mutations [37][38]
CBL RING E3 ubiquitin ligase SH3KBP1 [39] EGFR trafficking and signaling [40] Loss of function: missense mutations [41][42][43]
Autoimmune disorder associated to facial dysmorphism ITCH HECT E3 ubiquitin ligase TIEG1 [44]; SMN [45] Nuclear translocation of FOXP3 [44], translocation of SMN to Cajal body [45] Loss of function: frameshift mutations [46]

The abundance of the ubiquitin-related enzymes mutated in genetic disorders indicates that targeting the ubiquitin pathway might be of therapeutic use for a range of genetic diseases. However, at present, we lack a detailed knowledge on how monoubiquitin signals are generated and how they are decoded by the cell. This is challenged by the diversity and complexity of the ubiquitin pathway. Moreover, monoubiquitinated proteins might not have been accurately identified, because polyubiquitinated conjugates are recognized more efficiently by anti-ubiquitin specific antibodies. This leads to the underestimation of the pool of monoubiquitinated proteins present in the cell and challenges their characterization. The development of novel tools to purify monoubiquitinated proteins using high-affinity ubiquitin-binding domains and synthetic biology approaches to efficiently generate monoubiquitinated proteins can overcome these issues.

2. Development

It is also worth noting that when looking at the few drugs that were developed to target the ubiquitin pathway, most are meant only to inhibit its functioning. Several inhibitors targeting the ubiquitinating enzymes described in this review have been reported. Ubiquitin variants that block the E2-ubiquitin binding surface of the RING domain of CBL were shown to specifically inhibit the activity of CBL [47][48]. A high-throughput screening to identify ITCH inhibitors discovered that clomipramine, a common antidepressant drug, blocks ITCH autoubiquitination and affects the ability of ITCH to ubiquitinate its substrates [49]. Screening for the inhibitors of UBE2T/FANCL identified two compounds that sensitize cells to DNA crosslinking [50]. Pharmacological inhibition of USP8 was shown to effectively suppress ACTH synthesis in vitro without causing any significant cytotoxicity, indicating its potential for the management of ACTH hypersecretion in Cushing’s disease [51]. However, considering that the disease-associated alterations of the ubiquitin ligases and hydrolases are mostly loss of function, inhibitors targeting these enzymes would not be beneficial. This indicates that there is a need to develop novel strategies for targeted therapies of genetic diseases [52]. Several screens identified compounds activating PARKIN ubiquitin ligase activity [53]and enhancing mitophagy [54], such as the compound described in patent WO2018023029. While no in vivo validation is available for this compound yet, this demonstrates the feasibility of identification of E3 ligase activators, opening novel therapeutic options for patients with genetic disorders.

The analysis of the alterations of the ubiquitin system associated to genetic diseases generated evidence that monoubiquitination is a key process underlying the development of such diseases; highlighting the need for further research to identify new monoubiquitination-dependent signaling pathways as novel targets suitable for therapeutic approach of genetic diseases.


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    Sewduth, R.; Baietti, M.F. Monoubiquitin Signaling in Genetic Diseases. Encyclopedia. Available online: (accessed on 03 October 2022).
    Sewduth R, Baietti MF. Monoubiquitin Signaling in Genetic Diseases. Encyclopedia. Available at: Accessed October 03, 2022.
    Sewduth, Raj, Maria Francesca Baietti. "Monoubiquitin Signaling in Genetic Diseases," Encyclopedia, (accessed October 03, 2022).
    Sewduth, R., & Baietti, M.F. (2020, May 09). Monoubiquitin Signaling in Genetic Diseases. In Encyclopedia.
    Sewduth, Raj and Maria Francesca Baietti. ''Monoubiquitin Signaling in Genetic Diseases.'' Encyclopedia. Web. 09 May, 2020.