The Proteasome System in Health and Disease

Coux, Olivier; Zieba, Barbara A.; Meiners, Silke

doi:10.1007/978-3-030-38266-7_3

Cited by 20 publications

(23 citation statements)

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“…We therefore examined the protein abundance of different proteasome subunits. Proteasome complexes are comprised of the core particle, which process the substrates, and regulatory caps, which control substrate entry (Collins and Goldberg, 2017;Coux et al, 2020;Livneh et al, 2016;Motosugi and Murata, 2019;Rodriguez et al, 2007;Rousseau and Bertolotti, 2018). Notably, while subunits of the proteasome core particle (e.g.…”

Section: Proteasome Profiling Reveals An Altered Proteasome Activity and Distinct Cleavage Patterns In Lung Adenocarcinomamentioning

confidence: 99%

“…However, whether and how tumorigenic mechanisms modulate the immunoproteasome and constitutive proteasome functions to shape their microenvironments remains poorly understood. In addition to the core particle of the proteasome ,proteasome composition and the degradation landscape may be affected by specific regulatory particles such as the 19S regulatory complex (PSMC1-6 and PSMD1-14), or the regulatory caps PA28αβ (PSME1-2), PA28γ (PSME3) or PA200 (PSME4) (Collins and Goldberg, 2017;Coux et al, 2020;Rousseau and Bertolotti, 2018) that bind the catalytic core and affect gate opening and substrate selection. The 19S regulatory complex been shown to be pivotal for binding of ubiquitinated species and substrate unfolding, while the other regulatory subunits are suggested to have more specialized roles, including mediating inflammatory responses, histone degradation, and the response to DNA damage (Antoniou et al, 2012;Blickwedehl et al, 2012;Collins and Goldberg, 2017;Khor et al, 2006;Mandemaker et al, 2018aMandemaker et al, , 2018bQian et al, 2013;Rousseau and Bertolotti, 2018;Ustrell et al, 2002;Welk et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Javitt

Shmueli

et al. 2021

Preprint

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Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumor response to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.

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Section: Proteasome Profiling Reveals An Altered Proteasome Activity and Distinct Cleavage Patterns In Lung Adenocarcinomamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Javitt

Shmueli

et al. 2021

Preprint

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“…Proteasome-mediated protein degradation is a central pathway that controls the stability and function of numerous proteins in most cellular processes (Collins and Goldberg, 2017). Proteasomes comprise a family of protein complexes resulting from the association of different regulators/activators with the catalytic core, called the 20S proteasome (Rechsteiner and Hill, 2005;Coux et al, 2020). Among their many functions, it is now well established that proteasome complexes are associated with chromatin and enriched at specific sites in the genome (Geng and Tansey, 2012;Kito et al, 2020), thereby suggesting a direct role for chromatinassociated proteasome complexes in genomic processes (McCann and Tansey, 2014).…”

Section: Introductionmentioning

confidence: 99%

The 20S proteasome activator PA28γ controls the compaction of chromatin

Fesquet

Llères

Grimaud

et al. 2021

Journal of Cell Science

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PA28γ (also known as PSME3), a nuclear activator of the 20S proteasome, is involved in the degradation of several proteins regulating cell growth and proliferation and in the dynamics of various nuclear bodies, but its precise cellular functions remain unclear. Here, using a quantitative FLIM-FRET based microscopy assay monitoring close proximity between nucleosomes in living human cells, we show that PA28γ controls chromatin compaction. We find that its depletion induces a decompaction of pericentromeric heterochromatin, which is similar to what is observed upon the knockdown of HP1β (also known as CBX1), a key factor of the heterochromatin structure. We show that PA28γ is present at HP1β-containing repetitive DNA sequences abundant in heterochromatin and, importantly, that HP1β on its own is unable to drive chromatin compaction without the presence of PA28γ. At the molecular level, we show that this novel function of PA28γ is independent of its stable interaction with the 20S proteasome, and most likely depends on its ability to maintain appropriate levels of H3K9me3 and H4K20me3, histone modifications that are involved in heterochromatin formation. Overall, our results implicate PA28γ as a key factor involved in the regulation of the higher order structure of chromatin.

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“…In contrast the UPS is only capable of removing and recycling short half-life proteins from the cytoplasm, which control several signaling pathways [ 3 , 4 , 6 ]. Unfortunately, various types of disorders are connected to the reduced function of these self-degradative mechanisms such as cancer, diabetes, accelerated aging, fatty liver disease (FLD) and infectious, neurodegenerative and vascular diseases [ 7 , 8 , 9 ]. Notably, autophagy and UPS work together and complement each other for the effective degradation of cellular components which leads to normal homeostatic equilibrium during various internal or external effects [ 3 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Deubiquitinating Enzymes in the Various Forms of Autophagy

Csizmadia

Lőw

2020

IJMS

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Deubiquitinating enzymes (DUBs) have an essential role in several cell biological processes via removing the various ubiquitin patterns as posttranslational modification forms from the target proteins. These enzymes also contribute to the normal cytoplasmic ubiquitin pool during the recycling of this molecule. Autophagy, a summary name of the lysosome dependent self-degradative processes, is necessary for maintaining normal cellular homeostatic equilibrium. Numerous forms of autophagy are known depending on how the cellular self-material is delivered into the lysosomal lumen. In this review we focus on the colorful role of DUBs in autophagic processes and discuss the mechanistic contribution of these molecules to normal cellular homeostasis via the possible regulation forms of autophagic mechanisms.

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The Proteasome System in Health and Disease

Cited by 20 publications

References 451 publications

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

The 20S proteasome activator PA28γ controls the compaction of chromatin

The Role of Deubiquitinating Enzymes in the Various Forms of Autophagy

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