Ubiquitin–proteasome system as a target for anticancer treatment—an update

Kim, Yeon Jung; Lee, Yeonjoo; Shin, Hyungsoon; Hwang, Soo Hyun; Park, Jinyoung; Song, Eun Joo

doi:10.1007/s12272-023-01455-0

“…Ubiquitination is an important post-translational modification (PTM) that plays a key role in a wide range of cellular biological processes, including signal transduction [ 47 ], immune response [ 48 ], cancer [ 49 ], metabolism [ 50 ], etc. With a deeper understanding of ubiquitination, multiple forms of ubiquitination have been revealed, including K6-, K11-, K27-, K29-, K33-, K48- and K63-linked polyubiquitinations [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

Sui,

Zheng,

Fu

et al. 2024

PLoS Pathog

2

0

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The tripartite motif (TRIM) protein family is the largest subfamily of E3 ubiquitin ligases, playing a crucial role in the antiviral process. In this study, we found that TRIM72, a member of the TRIM protein family, was increased in neuronal cells and mouse brains following rabies lyssavirus (RABV) infection. Over-expression of TRIM72 significantly reduced the viral titer of RABV in neuronal cells and mitigated the pathogenicity of RABV in mice. Furthermore, we found that TRIM72 over-expression effectively prevents the assembly and/or release of RABV. In terms of the mechanism, TRIM72 promotes the K48-linked ubiquitination of RABV Matrix protein (M), leading to the degradation of M through the proteasome pathway. TRIM72 directly interacts with M and the interaction sites were identified and confirmed through TRIM72-M interaction model construction and mutation analysis. Further investigation revealed that the degradation of M induced by TRIM72 was attributed to TRIM72’s promotion of ubiquitination at site K195 in M. Importantly, the K195 site was found to be partially conserved among lyssavirus’s M proteins, and TRIM72 over-expression induced the degradation of these lyssavirus M proteins. In summary, our study has uncovered a TRIM family protein, TRIM72, that can restrict lyssavirus replication by degrading M, and we have identified a novel ubiquitination site (K195) in lyssavirus M.

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“…Ubiquitination is an important post-translational modification (PTM) that plays a key role in a wide range of cellular biological processes, including signal transduction [43], immune response [44], cancer [45], metabolism [46], etc. With a deeper understanding of ubiquitination, multiple forms of ubiquitination have been revealed, including K6-, K11-, K27-, K29-, K33-, K48- and K63-linked polyubiquitinations [47, 48].…”

Section: Discussionmentioning

confidence: 99%

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

Sui,

Zheng,

Fu

et al. 2023

Preprint

0

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The tripartite motif (TRIM) protein family is the largest subfamily of E3 ubiquitin ligases, playing a crucial role in the antiviral process. In this study, we found that TRIM72, a member of the TRIM protein family, was increased in neuronal cells and mouse brains following rabies lyssavirus (RABV) infection. Over-expression of TRIM72 significantly reduced the viral titer of RABV in neuronal cells and mitigated the pathogenicity of RABV in mice. Furthermore, we found that TRIM72 over-expression effectively prevents the release of RABV. In terms of the mechanism, TRIM72 promotes the K48-linked ubiquitination of RABV Matrix protein (M), leading to the degradation of M through the proteasome pathway. TRIM72 directly interacts with M and the interaction sites were identified and confirmed through TRIM72-M interaction model construction and mutation analysis. Further investigation revealed that the degradation of M induced by TRIM72 was attributed to TRIM72’s promotion of ubiquitination at site K195 in M. Importantly, the K195 site was found to be partially conserved among lyssavirus’s M proteins, and TRIM72 over-expression induced the degradation of these lyssavirus M proteins. In summary, our study has uncovered a TRIM family protein, TRIM72, that can restrict lyssavirus replication by degrading M, and we have identified a novel ubiquitination site (K195) in lyssavirus M.Author SummaryRabies, caused by lyssaviruses, most often by rabies virus, the most lethal zoonotic disease, is responsible for approximately 59000 human deaths globally each year. Lyssavirus M protein displays an essential role in lyssavirus assembly and budding. Here, we found that TRIM family protein TRIM72 directly interacts with lyssavirus M thereby promoting the K48-linked ubiquitination of M, leading to the degradation of M through the proteasome pathway, restricting lyssavirus release. Moreover, we identified a novel important ubiquitination site (K195) in lyssavirus M. Prior to our study, there had been no reports of a direct interaction between TRIM72 and viral proteins, an antiviral function of TRIM72 was proved in our study. It is possible that TRIM72 interacts and ubiquitinates other viral proteins from various viruses, which warrants further investigation. This research contributes to our understanding of how TRIM72 and other TRIM proteins play a role in defending against viral invasions and may inspire further research in this field.

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“…In the last decades, a large number of drugs/molecules targeting the ubiquitination machinery have entered clinical trials against solid and hematological malignancies (for a review, the reader is referred to [ 51 , 110 , 122 , 125 , 126 , 152 , 153 ]) and several trials have been conducted and are currently ongoing to assess their safety, tolerability and therapeutic activity in cancer ( ). Within this growing number of trials, only a few have been completed and results are currently available ( Table 2 ).…”

Section: Targeting Ubiquitination As a Therapeutic Approach To Cancer...mentioning

confidence: 99%

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Spano,

Catara

2023

Cells

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Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects on various signaling pathways. Ubiquitination can alter the molecular functions of tagged substrates with respect to protein turnover, biological activity, subcellular localization or protein–protein interaction. As a result, a wide variety of cellular processes are under ubiquitination-mediated control, contributing to the maintenance of cellular homeostasis. It follows that the dysregulation of ubiquitination reactions plays a relevant role in the pathogenic states of human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, the enzymes of the ubiquitin–proteasome system (UPS), including E3 ubiquitin ligases and deubiquitinases (DUBs), have attracted attention as novel druggable targets for the development of new anticancer therapeutic approaches. This perspective article summarizes the peculiarities shared by the enzymes involved in the ubiquitination reaction which, when deregulated, can lead to tumorigenesis. Accordingly, an overview of the main pharmacological interventions based on targeting the UPS that are in clinical use or still in clinical trials is provided, also highlighting the limitations of the therapeutic efficacy of these approaches. Therefore, various attempts to circumvent drug resistance and side effects as well as UPS-related emerging technologies in anticancer therapeutics are discussed.

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Ubiquitin–proteasome system as a target for anticancer treatment—an update

Cited by 19 publications

References 156 publications

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

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