Deep analysis of the USP18-dependent ISGylome and proteome unveils important roles for USP18 in tumour cell antigenicity and radiosensitivity

Pinto-Fernández, Adán; Salio, Mariolina; Partridge, Thomas; Chen, J; Vere, George; Greenwood, Helene; Olie, Cyriel Sebastiaan; Damianou, Andreas; Scott, Hannah C.; Diaz-Saez, L.; Smith, Paul; Lopez, Carlos G.; Huber, K.; Muschel, Ruth J.; Borrow, Persephone; Cerundolo, Vincenzo; Kessler, Benedikt M.

doi:10.1101/2020.03.31.005629

Cited by 4 publications

(3 citation statements)

References 71 publications

(110 reference statements)

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“…This revealed that about 95% of identified di-Gly-modified peptides in human cells derive from ubiquitylation, rather than neddylation [53], evidence finding that was recently confirmed by global and selective quantification of NEDD8-modified proteins [72]. Since ISGylation appears to be even less frequent and occurs only in response to interferon (IFN)-α/β stimulation [100][101][102][103], K-GG remnant profiling remains a very valuable tool for studying ubiquitin signaling. Kim et al further established that an unexpectedly high fraction of proteins were deubiquitylated after proteasome inhibition, likely reflecting ubiquitin recycling from monoubiquitylated proteins being used for polyubiquitin chain formation on other proteins [104,105].…”

Section: Significance Of Ubiquitinomics In Cell Biology and In Drug D...mentioning

confidence: 92%

Ubiquitinomics: History, methods, and applications in basic research and drug discovery

2022

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The ubiquitin‐proteasome system (UPS) was discovered about 40 years ago and is known to regulate a multitude of cellular processes including protein homeostasis. Ubiquitylated proteins are recognized by downstream effectors, resulting in alterations of protein abundance, activity, or localization. Not surprisingly, the ubiquitylation machinery is dysregulated in numerous diseases, including cancers and neurodegeneration. Mass spectrometry (MS)‐based proteomics has emerged as a transformative technology for characterizing protein ubiquitylation in an unbiased fashion. Here, we provide an overview of the different MS‐based approaches for studying protein ubiquitylation. We review various methods for enriching and quantifying ubiquitin modifications at the peptide or protein level, outline MS acquisition, and data processing approaches and discuss key challenges. Finally, we examine how MS‐based ubiquitinomics can aid both basic biology and drug discovery research.

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Section: Significance Of Ubiquitinomics In Cell Biology and In Drug D...mentioning

confidence: 92%

Ubiquitinomics: History, methods, and applications in basic research and drug discovery

2022

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“…The combination of modulating DUB activity with proteomic ubiquitination profiling has been recently applied in other cancer contexts to identify new potential treatment paradigms. For example, Kessler and co-workers used an advanced chemical proteomics approach identify a set of oncogenic substrates of USP18 that appeared to be more susceptible to irradiation, suggesting that selective inhibition of USP18 could sensitise chronic myeloid leukaemia patients to radiotherapy [116]. Practical and robust methods to profile the substrates of UCHL1 across diverse disease contexts will be of great interest to the DUB drug discovery and chemical biology community, for which selective inhibitors such as IMP-1710 will be powerful tools.…”

Section: Future Directions For Uchl1 As a Target In Breast Cancermentioning

confidence: 99%

UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

et al. 2021

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Breast cancer has the highest incidence and death rate among cancers in women worldwide. In particular, metastatic estrogen receptor negative (ER–) breast cancer and triple-negative breast cancer (TNBC) subtypes have very limited treatment options, with low survival rates. Ubiquitin carboxyl terminal hydrolase L1 (UCHL1), a ubiquitin C-terminal hydrolase belonging to the deubiquitinase (DUB) family of enzymes, is highly expressed in these cancer types, and several key reports have revealed emerging and important roles for UCHL1 in breast cancer. However, selective and potent small-molecule UCHL1 inhibitors have been disclosed only very recently, alongside chemical biology approaches to detect regulated UHCL1 activity in cancer cells. These tools will enable novel insights into oncogenic mechanisms driven by UCHL1, and identification of substrate proteins deubiquitinated by UCHL1, with the ultimate goal of realising the potential of UCHL1 as a drug target in breast cancer.

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“…In IFN-treated acute myeloid leukemia cell lines, depletion of USP18 inhibited cell proliferation and induced apoptosis. USP18 -KO cells are sensitive to irradiation-induced apoptosis, suggesting that USP18 is a potential therapeutic target [ 106 ]. Some studies have revealed the molecular mechanisms involved in the USP18-mediated suppression of apoptosis in IFN stimuli.…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee

Kim

Hwang

et al. 2021

IJMS

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The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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Deep analysis of the USP18-dependent ISGylome and proteome unveils important roles for USP18 in tumour cell antigenicity and radiosensitivity

Cited by 4 publications

References 71 publications

Ubiquitinomics: History, methods, and applications in basic research and drug discovery

Ubiquitinomics: History, methods, and applications in basic research and drug discovery

UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

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