Efficiency of the four proteasome subtypes to degrade ubiquitinated or oxidized proteins

Habib, Joanna Abi; Plaen, Etienne De; Stroobant, Vincent; Živković, Dušan; Bousquet, Marie‐Pierre; Guillaume, Benoı̂t; Wahni, Khadija; Messens, Joris; Busse, Antonia; Vigneron, Nathalie; Eynde, Benoı̂t J. Van den

doi:10.1038/s41598-020-71550-5

Cited by 36 publications

(48 citation statements)

References 84 publications

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“…Unlike the ubiquitously expressed constitutive proteasome, the immunoproteasome is predominantly present in hematolymphoid cells (4,5) and is typically only induced in other cells by inflammatory stimuli-like IFNg (6). The immunoproteasome possesses a high capacity for degradation of oxidized, misfolded, and aggregated proteins to maintain homeostasis under acute cellular stress (7).…”

Section: Introductionmentioning

confidence: 99%

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

Sanderson

Friese-Hamim

Walter-Bausch

et al. 2021

Molecular Cancer Therapeutics

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Large multifunctional peptidase 7 (LMP7/b5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally bioavailable, potent, reversible and highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in multiple myeloma xenograft models, including a novel model of the human bone niche of multiple myeloma. M3258 treatment led to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in multiple myeloma cells both in vitro and in vivo. Furthermore, M3258 showed superior antitumor efficacy in selected multiple myeloma and mantle cell lymphoma xenograft models compared with the approved nonselective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in patients with multiple myeloma (NCT04075721).

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Section: Introductionmentioning

confidence: 99%

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

Sanderson

Friese-Hamim

Walter-Bausch

et al. 2021

Molecular Cancer Therapeutics

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“…It has been shown before by protein-protein interactomes and bioinformatics analyses [33,34], and it is currently observed in both directions: proteostasis is not only affected by oxidative stress, but it seems to protect the reconstituted cells from oxidative lysis and ROS accumulation. Interestingly, lower oxidative RBC lysis, after treatment with the Hb-targeting phenylhydrazine, was observed in the proteasome enriched βThal + samples, implying a role for the proteasome in the degradation of oxidized Hb [35].…”

Section: Stored Rbc Features In Recipient Plasma and Temperaturementioning

confidence: 89%

The Post-Storage Performance of RBCs from Beta-Thalassemia Trait Donors Is Related to Their Storability Profile

Anastasiadi

Paronis

Arvaniti

et al. 2021

IJMS

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Blood donors with beta-thalassemia traits (βThal+) have proven to be good “storers”, since their stored RBCs are resistant to lysis and resilient against oxidative/proteotoxic stress. To examine the performance of these RBCs post-storage, stored βThal+ and control RBCs were reconstituted in plasma donated from transfusion-dependent beta-thalassemic patients and healthy controls, and incubated for 24 h at body temperature. Several physiological parameters, including hemolysis, were evaluated. Moreover, labeled fresh/stored RBCs from the two groups were transfused in mice to assess 24 h recovery. All hemolysis metrics were better in the group of heterozygotes and distinguished them against controls in the plasma environment. The reconstituted βThal+ samples also presented higher proteasome activity and fewer procoagulant extracellular vesicles. Transfusion to mice demonstrated that βThal+ RBCs present a marginal trend for higher recovery, regardless of the recipient’s immune background and the RBC storage age. According to correlation analysis, several of these advantageous post-storage characteristics are related to storage phenotypes, like the cytoskeleton composition, low cellular fragility, and enhanced membrane proteostasis that characterize stored βThal+ RBCs. Overall, it seems that the intrinsic physiology of βThal+ RBCs benefits them in conditions mimicking a recipient environment, and in the circulation of animal models; findings that warrant validation in clinical trials.

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“…The iP has been shown to prevent the accumulation of harmful protein aggregates under cytokine-induced oxidative stress due to increased efficiency in protein degradation compared to the cP [ 78 , 79 , 80 , 81 , 82 ], even though this aspect is still a matter of debate [ 83 , 84 ]. In addition, the 20S core particle has been demonstrated to dissociate from the 26S proteasome under stress conditions, with the iP containing 20S being more efficient than its standard counterpart at degrading oxidized proteins in an ATP- and ubiquitin-independent manner [ 58 , 85 ]. Supporting this notion, expression of the iP is upregulated through the mTOR pathway to prevent the accumulation of misfolded or damaged proteins [ 82 ].…”

Section: The Immunoproteasome: a Proteasomal Variant Linked To The Hematopoietic Systemmentioning

confidence: 99%

Immunoproteasome Function in Normal and Malignant Hematopoiesis

Tubío-Santamaría

Ebstein

Heidel

et al. 2021

Cells

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The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

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Efficiency of the four proteasome subtypes to degrade ubiquitinated or oxidized proteins

Cited by 36 publications

References 84 publications

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models

The Post-Storage Performance of RBCs from Beta-Thalassemia Trait Donors Is Related to Their Storability Profile

Immunoproteasome Function in Normal and Malignant Hematopoiesis

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