Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes

Conole, Daniel; Mondal, Milon; Majmudar, Jaimeen D.; Tate, Edward W.

doi:10.3389/fchem.2019.00876

Cited by 26 publications

(23 citation statements)

References 46 publications

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“… 2 However, they are not selective between DUBs and limited to cell-free applications, highlighting a need for complementary small-molecule ABPs to profile DUB activity in intact cells. 3 , 4 …”

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confidence: 99%

Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity

et al. 2020

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Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme that is proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis. Herein we report the discovery of the most potent and selective UCHL1 probe (IMP-1710) to date based on a covalent inhibitor scaffold and apply this probe to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration in cells. We further demonstrate that potent and selective UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting the potential of UCHL1 as a potential therapeutic target in fibrotic diseases.

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confidence: 99%

Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity

et al. 2020

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“…Promising novel tools to study the UPS in an intact cellular context are activity-based probes (ABPs). In recent years, a number of ABPs have been developed to study the ubiquitylation cascade [73], DUBs [74], and the proteasome [75,76]. Although potentially powerful, several ABPs suffer from limitations such as limited cell permeability and irreversible inhibition of the target enzymes, which means they only provide a snapshot of the enzymatic activity queried at any given time.…”

Section: Open Accessmentioning

confidence: 99%

Proteostatic regulation in neuronal compartments

Giandomenico

Álvarez-Castelao

Schuman

2022

Trends in Neurosciences

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Neurons continuously adapt to external cues and challenges, including stimulation, plasticity-inducing signals and aging. These adaptations are critical for neuronal physiology and extended survival. Proteostasis is the process by which cells adjust their protein content to achieve the specific protein repertoire necessary for cellular function. Due to their complex morphology and polarized nature, neurons possess unique proteostatic requirements. Proteostatic control in axons and dendrites must be implemented through regulation of protein synthesis and degradation in a decentralized fashion, but at the same time, it requires integration, at least in part, in the soma. Here, we discuss current understanding of neuronal proteostasis, as well as open questions and future directions requiring further exploration. The challenge of regulating a distant proteomeMost catalyzed chemical reactions inside cells depend on protein levels, and fine-tuning protein concentrations is key to ensure proper cellular function. Because throughout the cellular lifespan proteins accumulate damage, become dysfunctional and need to be replaced continually, protein synthesis and protein turnover are central to cellular physiology and function. The dynamic regulation of a balanced and functional proteome (i.e., proteostasis) concerns all proteins whose levels need to be adjusted in space and time in response to intracellular and extracellular cues. Thus, the specific parameters of cellular proteostasis vary across cell types and states. However, cellular proteostasis invariably relies on the precise control of protein synthesis, folding and conformational maintenance, post-translational modifications (PTMs), degradation, and secretion [1]. Precise control of these parameters is already challenging in cells that have little or no polarity, but becomes a particularly impressive feat for highly polarized cells, such as neurons.Neurons stand out from all other cell types in their unique morphology and high degree of compartmentalization; characteristics that are central to neuronal computation. Often, extrinsic signals are spatially localized so that only a confined portion of the neuron receives a certain signal, with the neuronal portion being, for instance, a cluster of dendrites (influenced by a neuromodulator), a single dendritic branch, a synaptic neighborhood, or even an individual synapse. How these local signals are transmitted to the somata remains largely unknown. Work over the last two decades has shown that neurons have the capacity to tune their proteome locally through regulation of local protein synthesis, degradation, and PTMs to regulate multiple aspects of dendritic and axonal biology [2]. Nevertheless, to date, we still lack a comprehensive understanding of how different cellular degradation pathways interact with the protein synthesis machinery to shape and maintain the local proteome.In this review, we discuss current understanding of neuronal local proteostatic regulation, and key knowledge gaps in the field. We also com...

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“…Related chemical approaches were also successfully applied to generate ubiquitin-based probes. [123][124][125][126][127] These efforts have facilitated the discovery of inhibitors that can modulate the enzymatic ubiquitination and deubiquitination processes.…”

Section: Summary and Perspectivementioning

confidence: 99%