The Logic of the 26S Proteasome

Collins, Galen Andrew; Goldberg, Alfred L.

doi:10.1016/j.cell.2017.04.023

Cited by 684 publications

(686 citation statements)

References 139 publications

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“…The 26S proteasome is a major component of the ubiquitin proteasome pathway, which is responsible for more than 80% of protein degradation in mammalian cells [8]. Since cancer cells require the ubiquitin proteasome pathway to permanently activate pro-tumor signal cascades, which promote cell cycle progression and prevents cell death resulting from aberrant stress [9], the use of inhibitors targeting the ubiquitin proteasome pathway is an attractive strategy for treating different cancers [10,11].…”

Section: Introductionmentioning

confidence: 99%

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

Wang

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. Methods: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. Results: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. Conclusions: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

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Section: Introductionmentioning

confidence: 99%

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

Wang

Zheng

et al. 2018

Cell Physiol Biochem

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“…This is particularly detrimental to neurons because they cannot dilute toxic aggregates by mitotic cell division [4]. The UPS enzymatic cascade consists of two discrete and successive steps: first the covalent tagging of the substrate protein by a poly-ubiquitin chain; second, the subsequent degradation of the tagged protein by the 26S proteasome [5]. In eukaryotic cells several enzymes including ubiquitin-activating enzyme (E1 ubiquitin activase), ubiquitin-conjugating enzyme (E2 ubiquitin conjugase), and ubiquitin ligase (E3 ubiquitin ligase) conjugate molecules of ubiquitin to the target lysine on the substrate protein.…”

Section: The Ubiquitin Proteasome System (Ups) In Neurodegenerative Dmentioning

confidence: 99%

“…The data so far show that phosphorylation regulates multiple components of the 26S proteasome complex, and this could impact on several steps in the proteolytic process. For example, PKA activation enhances the activity of ATPase subunits Rpt1–6 [25,41] that are involved in protein engagement of the proteasome as well as in the unfolding and translocation of the protein to the 20S core for degradation (Box 1) [5]. Furthermore, PKA was reported to increase 26S proteasome abundance and stability by inducing the association of the 20S core with the 19S regulatory complex, presumably leading to facilitated protein degradation in cell lines and in vivo in canine hearts [41,42,46,52].…”

Section: Direct Activation Of 26s Proteasome Functionmentioning

confidence: 99%

“…It comprises two components: a 19S regulatory particle (RP) and a 20S core particle (CP) that carries out the catalytic activity [5]. The 20S CP is a barrel-shaped structure composed of 28 subunits stacked in four rings with two inner β rings that are flanked by two outer a rings.…”

Section: Figure 1 Key Figurementioning

confidence: 99%

“…The majority of 20S proteasomes are capped by one or two 19S RPs, composed of 19 different subunits arranged in two distinct subcomplexes termed the base and the lid. The 19S complex is responsible for various biochemical functions, including the recognition of substrates and the binding, deubiquitination, unfolding, and translocation of substrates to the 20S chamber where the protein undergoes irreversible degradation [5,99]. …”

Section: Figure 1 Key Figurementioning

confidence: 99%

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Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

Myeku

Duff

2018

Trends in Molecular Medicine

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Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction. The range of candidates might address the need forregion-,cell-,oreven cellular compartment-specific modulation. Given the array of clinical and experimental drugs targeting cAMP/cGMP signaling, we propose that proteasome activators targeting secondary messengers might be exploited as novel agents for the treatment or prevention of some neurodegenerative diseases.

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The 19S proteasome subunit Rpt5 reversibly associates with cold‐stable microtubules in glial cells at low temperatures

Flores-Martín

Palandri

et al. 2022

FEBS Letters

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The ubiquitin–proteasome system (UPS) degrades intracellular proteins through the 26S proteasome. We analysed how cold stress affects the UPS in glial cells. Together with a reduction in the 20S proteolytic activity and increased levels of polyubiquitinated proteins, exposure of glial cell cultures to cold induces a partial disassembly of the 26S proteasome. In particular, we found that Rpt5, a subunit of the 19S proteasome, relocates to cold‐stable microtubules, although no apparent cytoskeletal redistribution was detected for other analysed subunits of the 19S or 20S complexes. Furthermore, we demonstrate that both the expression of the microtubule‐associated protein MAP6 and the post‐translational acetylation of α‐tubulin modulate the association of Rpt5 with microtubules. This reversible association could be related to functional preservation of the proteolytic complex during cold stress.

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The Logic of the 26S Proteasome

Cited by 684 publications

References 139 publications

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

The 19S proteasome subunit Rpt5 reversibly associates with cold‐stable microtubules in glial cells at low temperatures

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