Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk, Vanessa; Coux, Olivier; Kleene, Vera; Abéza, Claire; Trümbach, Dietrich; Eickelberg, Oliver; Meiners, Silke

doi:10.1074/jbc.m116.717652

Cited by 55 publications

(65 citation statements)

References 69 publications

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“…Although PA28γ interacts with the 20S proteasome, we identified only the α6 subunit (PSMA1) in the conditions used. However, we found all subunits with high H/L ratios when PA28γ pulldowns were performed in the presence of proteasome inhibitors (data not shown), confirming that PA28γ/20S proteasome interaction is labile (31) and is stabilized upon proteasome inhibition (11,43).…”

Section: Discussionmentioning

confidence: 53%

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PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

Jonik-Nowak

Menneteau

Fesquet

et al. 2017

Preprint

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PA28γ is a nuclear activator of the 20S proteasome involved in the regulation of several essential cellular processes, such as cell proliferation, apoptosis, nuclear dynamics and cellular stress response. Unlike the 19S regulator of the proteasome, which specifically recognizes ubiquitylated proteins, PA28γ promotes the degradation of several substrates by the proteasome in an ATP- and ubiquitin-independent manner. However its exact mechanisms of action are unclear and likely to involve additional partners that remain to be identified. Here we report the identification of the first cofactor of PA28γ, PIP30/FAM192A. PIP30 binds directly and specifically via its C-terminal end and in an interaction stabilized by casein kinase 2 phosphorylation to both free and 20S proteasome-associated PA28γ. Its recruitment to proteasome-containing complexes depends on PA28γ and its expression increases the association of PA28γ with the 20S proteasome in cells. Further dissection of its possible roles shows that PIP30 alters PA28γ-dependent activation of peptide degradation by the 20S proteasome in vitro and negatively controls in cells the presence of PA28γ in Cajal Bodies by inhibition of its association with the key Cajal body component coilin. Altogether, our data show that PIP30 deeply affects PA28γ interactions with cellular proteins, including 20S proteasome, demonstrating that it is an important regulator of PA28γ in cells and thus a new player in the control of the multiple functions of the proteasome within the nucleus.Significance StatementThe 20S proteasome is a key actor of the control of protein levels and integrity in cells. To perform its multiple functions, it works with a series of regulators, among which a nuclear complex called PA28γ. In particular, PA28γ participates in the regulation of cell proliferation and nuclear dynamics. We describe here the characterization of a novel protein, PIP30/FAM192A, which binds tightly to PA28γ and favors its interaction with the 20S proteasome while inhibiting its association with coilin, a central component of nuclear Cajal bodies. Thus PIP30/FAM192A critically controls the interactome and consequently the functions of PA28γ, and appears to be a new player in the fine regulation of intracellular proteostasis in the cell nucleus.

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Section: Discussionmentioning

confidence: 53%

“…However, they are also found in hybrid proteasomes, i.e. 20S proteasome bound to a PA28 heptamer on one end and a 19S complex on the other end (11) and are thus likely to also participate in ATPdependent degradation of ubiquitylated proteins.…”

Section: Introductionmentioning

confidence: 99%

PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

Jonik-Nowak

Menneteau

Fesquet

et al. 2017

Preprint

Self Cite

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“…The 20S may associate with other activators/inhibitors, such as the proteasome activator PA200 or the proteasome regulator PI31, forming alternative proteasome complexes with different functions and substrate specificities. While PA200 works in an ubiquitin-and ATP-independent manner unless in complex with 20S and 19S, the function of PI31 is still not well characterized (Fort et al, 2015;Welk et al, 2016). Interestingly, seed storage proteins, which are abundant in dry seeds and are degraded during germination to sustain seedling growth, are the major forms of carbonylated (oxidized) proteins and thus likely degraded by the 20S during germination (Job et al, 2005).…”

Section: Aba Inhibits Seed Germination At 32°c Through Downregulationmentioning

confidence: 99%

ABA‐dependent inhibition of the ubiquitin proteasome system during germination at high temperature in Arabidopsis

et al. 2016

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During germination, endogenous and environmental factors trigger changes in the transcriptome, translatome and proteome to break dormancy. In Arabidopsis thaliana, the ubiquitin proteasome system (UPS) degrades proteins that promote dormancy to allow germination. While research on the UPS has focused on the identification of proteasomal substrates, little information is known about the regulation of its activity. Here we characterized the activity of the UPS during dormancy release and maintenance by monitoring protein ubiquitination and degradation of two proteasomal substrates: Suc-LLVY-AMC, a well characterized synthetic substrate, and FUSCA3 (FUS3), a dormancy-promoting transcription factor degraded by the 26S proteasome. Our data indicate that proteasome activity and protein ubiquitination increase during imbibition at optimal temperature (21°C), and are required for seed germination. However, abscisic acid (ABA) and supraoptimal temperature (32°C) inhibit germination by dampening both protein ubiquitination and proteasome activity. Inhibition of UPS function by high temperature is reduced by the ABA biosynthesis inhibitor, fluridone, and in ABA biosynthetic mutants, suggesting that it is ABA dependent. Accordingly, inhibition of FUS3 degradation at 32°C is also dependent on ABA. Native gels show that inhibition of proteasome activity is caused by interference with the 26S/30S ratio as well as free 19S and 20S levels, impacting the proteasome degradation cycle. Transfer experiments show that ABA-mediated inhibition of proteasome activity at 21°C is restricted to the first 2 days of germination, a time window corresponding to seed sensitivity to environmental and ABA-mediated growth inhibition. Our data show that ABA and high temperature inhibit germination under unfavourable growth conditions by repressing the UPS.

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“…REGγ is important for responses to genotoxic and oxidative stress as well as the impairment of proteasome function, which is for example the case in neurodegenerative diseases (25). Interestingly, it was shown that cellular REGγ is massively recruited to proteasomes after non-toxic treatment with proteasome inhibitors (26). Furthermore, recently, a specific interactor of REGγ has been identified, also called PIP30, which positively modulates the interaction of REGγ to the 20S proteasome complex and alters the selectivity of the REGγ/20S proteasome complex towards different peptides (27).…”

Section: Introductionmentioning

confidence: 99%

Tumors escape immunosurveillance by overexpressing the proteasome activator REGγ

Boulpicante

Darrigrand

Pierson

et al. 2019

Preprint

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The success of CD8+ T cell based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during the pioneer round of mRNA translation (pioneer translation products, or PTPs) can be a potentially important source of tumor specific peptides, given the presence of aberrant splicing and transcription associated with oncogenesis. Here we show that cancer cells up-regulation of the REGγ proteasome regulator results in increased destruction of PTP-derived peptides in the nucleus thus subverting immunosurveillance. These findings add to understanding of the role of REGγ in antigen processing and identify it as a druggable target for improving the efficacy of cancer immunotherapy. SignificanceWith the clear success of CD8+ T cell based immunotherapy, it is critical to understand i) how tumor cells generate MHC-I peptide antigens? and ii) the various mechanisms used by cancer cells to evade immunosurveillance. One of them is to up-regulate the REGγ proteasome regulator which results in an increase destruction of MHC-I peptides in the nucleus thus subverting immunosurveillance.Cellular immune responses against cancer cells expressing non-self epitopes require the activation of CD8+ T cells by professional antigen presenting cells (pAPCs), which take up external peptide material and present it on their major histocompatibility complex class I (MHC-I) molecules as part of a process called cross-presentation (1). The MHC-I direct and cross-presentation pathways are fundamental processes for the detection and elimination of cells that pose a threat to the host. In recent years, it has been suggested that peptides that are directly presented to the MHC-I restricted pathway are not derived from the degradation of full-length proteins but from so-called defective ribosomal products, or DRiPs (2). In addition, some MHC-I-bound peptides are generated by cryptic translation, which refers to polypeptides synthesized in the cell via non-conventional translational mechanisms.These are either peptides encoded by introns, intron/exon junctions, 5' and 3' untranslated regions, alternate translational reading frames, or even fusion peptides generated by the proteasome (3-6).These observations have led to a shift in focus towards the notion that the degradation of full-length proteins is not the only critical process for antigen production. More recently, we have shown that the antigen presentation is equivalent whether the peptide is expressed from an intron or from an exon is supported by so-called pioneer translation products (PTPs) (7), which are produced by a translation event distinct from canonical translation prior to mRNA splicing. The PTP model is appealing because it offers an explanation of how the immune system "tolerates" tissue-dependent alternative splicing products. By first examining how direct presentation applies to viral mechanisms of ...

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Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Cited by 55 publications

References 69 publications

PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

ABA‐dependent inhibition of the ubiquitin proteasome system during germination at high temperature in Arabidopsis

Tumors escape immunosurveillance by overexpressing the proteasome activator REGγ

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