A Practical Review of Proteasome Pharmacology

Thibaudeau, Tiffany A.; Smith, David M.

doi:10.1124/pr.117.015370

Cited by 258 publications

(244 citation statements)

References 267 publications

(361 reference statements)

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“…For example, cancer cells for its high metabolic activity often encounter ER stress due to accumulation of misfolded and aggregated proteins exerting an unfolded protein response (UPR) [62]. Such protein aggregates can bind and stabilize an inactive closed conformation of the 26S proteasome [63]. Additionally, UPS alone is not capable enough to alleviate UPR and resulting in apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Gain¹,

Malik²,

Bhattacharjee³

et al. 2019

Preprint

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26 Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation 27 and development of several B-cell lymphomas particularly those are generated in an immuno-28 compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating 29 multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be 30 ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is 31 surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal 32 mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, 33 we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival 34 particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition 35 by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-36 expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family 37 oncoproteins -EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C 38 degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal 39 pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked 40 polyubiquitinated, colocalized with the autophagy-lsyosomal fraction in the cytoplasm and 41 participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We 42 further show that the degradation signal is present at the first 50 residues of the N-terminal region 43 of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral 44 oncoprotein, increases transcriptional activation of both latent and lytic gene expression and 45 induces viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers 46 rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV 47 associated B-cell lymphomas, where EBNA3C is expressed. 48 49 50 3 | P a g e 51 Author Summary 52 Epstein-Barr virus (EBV) establishes latent infection in B-lymphocytes and is associated with 53 a number of human malignancies, both of epithelial and lymphoid origin. EBV encoded EBNA3 54 family of nuclear latent antigens comprising of EBNA3A, EBNA3B, and EBNA3C are unique to 55 immunoblastic lymphomas. While EBNA3A and EBNA3C are involved in blocking many important 56 tumor suppressive mechanisms, EBNA3B exhibits tumor suppressive functions. Although EBNA3 57 proteins, in particular EBNA3C, interact with and employ different protein degradation machineries 58 to induce B-cell lymphomagenesis, these viral proteins are extremely stable in growing B-59 lymphocytes. To this end, we now demonstrate that proteasomal inhibition leads to specifically 60 degradation of oncogenic EBNA3A and EBNA3C proteins, whereas EBNA3B remains unaffected. 61 Upon proteasomal inhibition, EBNA3C degradation occurs via autophagy-lysosomal pathway, 62 thro...

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Section: Discussionmentioning

confidence: 99%

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Gain¹,

Malik²,

Bhattacharjee³

et al. 2019

Preprint

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“…Bortezomib allows cellular accumulation of misfolded or unfolded damaged protein, or unprocessed protein, that cannot be degraded or recycled or form a processed protein via proteasome pathway. Excessive build-up of such nonfunctional proteins leads to cell death (47). As plasma cells are actively engaged in producing autoantibodies in MG, significant accumulation of damaged and unprocessed proteins occurs, due to their rapid transcription and translation activities.…”

Section: Proteasome-targeting Inhibitorsmentioning

confidence: 99%

New Approaches to Targeting B Cells for Myasthenia Gravis Therapy

Huda

2020

Front. Immunol.

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Current therapies for myasthenia gravis (MG) are limited, and many investigations have recently focused on target-specific therapies. B cell-targeting monoclonal antibody (mAb) therapies for MG are increasingly attractive due to their specificity and efficacy. The targeted B cell biomarkers are mainly the cluster of differentiation (CD) proteins that mediate maturation, differentiation, or survival of pathogenic B cells. Additional B cell-directed therapies include non-specific peptide inhibitors that preferentially target specific B cell subsets. The primary goals of such therapies are to intercept autoantibodies and prevent the generation of an inflammatory response that contributes to the pathogenesis of MG. Treatment of patients with MG using B cell-directed mAbs, antibody fragments, or selective inhibitors have exhibited moderate to high efficacy in early studies, and some of these therapies appear to be highly promising for further drug development. Numerous other biologics targeting various B cell surface molecules have been approved for the treatment of other conditions or are either in clinical trials or preclinical development stages. These approaches remain to be tested in patients with MG or animal models of the disease. This review article provides an overview of B cell-targeted treatments for MG, including those already available and those still in preclinical and clinical development. We also discuss the potential benefits as well as the shortcomings of these approaches to development of new therapies for MG and future directions in the field.

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“…To determine whether increased degradation also contributed to the more rapid disappearance of proANP from Pam Myh6-cKO/cKO myocytes, cultures of both genotypes were treated with methylamine/ammonium chloride to raise luminal pH and inhibit lysosomal degradation, with MG132 or Bortezomib to inhibit proteasomal degradation or with E64 to inhibit calpain cleavage ( Fig. 5D) (51). None of these treatments increased the proANP content of control or Pam Myh6-cKO/cKO atrial myocytes.…”

Section: Increased Basal Secretion and Turnover Of Proanp By Pam Myh6mentioning

confidence: 99%

A Single Membrane Protein Required for Atrial Secretory Granule Formation

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Luxmi

Powers

et al. 2020

Preprint

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Conflicts:The authors declare no conflict of interest.Classification: Biological Sciences (major); Cell Biology (minor) Abstract:The discovery of atrial secretory granules and the natriuretic peptides stored in them identified the atrium as an endocrine organ. Although neither atrial nor brain natriuretic peptide (ANP, BNP) is amidated, the major membrane protein in atrial granules is Peptidylglycine -Amidating Monooxygenase (PAM), an enzyme essential for amidated peptide biosynthesis. Mice lacking cardiomyocyte PAM (Pam Myh6-cKO/cKO ) are viable, but a gene dosage-dependent drop in atrial ANP and BNP content occurred. Ultrastructural analysis of adult Pam Myh6-cKO/cKO atria revealed a 20-fold drop in the volume fraction of secretory granules and a decrease in peripherally localized Golgi complexes. When primary cultures of Pam 0-Cre-cKO/cKO atrial myocytes (PAM floxed, no Cre recombinase) were transduced with Cre-GFP lentivirus, PAM protein levels dropped, followed by a decline in proANP levels. Expression of exogenous PAM in Pam Myh6-cKO/cKO atrial myocytes produced a dose-dependent increase in proANP content. Strikingly, rescue of proANP content did not require the monooxygenase activity of PAM. Unlike many prohormones, atrial proANP is stored intact and its basal secretion is stimulated by drugs that inhibit Golgi-localized Arf activators. Increased basal secretion of proANP was a major contributor to its reduced levels in Pam Myh6-cKO/cKO myocytes; the inability of these drugs to inhibit basal proANP secretion by Pam Myh6-cKO/cKO myocytes revealed a role for COPI-mediated recycling of PAM to the endoplasmic reticulum. Analysis of atrial coated vesicles and the ability PAM to make fluorescently-tagged proANP accumulate in the cis-Golgi region of cells lacking secretory granules revealed a non-catalytic role for PAM in soluble cargo trafficking early in the secretory pathway. Significance:Transmission electron microscopy of atrial cardiomyocytes revealed dense granules resembling those in endocrine cells and neurons, leading to the discovery of the natriuretic peptides stored in these granules. Subsequent studies revealed features unique to atrial granules, including high level expression of Peptidylglycine -Amidating Monooxygenase (PAM), an enzyme required for the synthesis of many neuropeptides, but not for the synthesis of natriuretic peptides. The discovery that atrial myocytes lacking PAM are unable to produce granules and that PAM lacking its monooxygenase activity can rescue granule formation provides new information about the proANP secretory pathway. A better understanding of the unique features of atrial cell biology should provide insight into atrial fibrillation, the most common cardiac arrhythmia, atrial amyloidosis and heart failure. RESULTS Secretory granules are rarely seen in the atria of Pam Myh6-cKO/cKO miceWe turned to transmission electron microscopy to determine whether the drop in proANP levels observed in the atria of Pam Myh6-cKO/cKO mice (3) were accompanied by a decrease in the num...

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A Practical Review of Proteasome Pharmacology

Cited by 258 publications

References 267 publications

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

Proteasomal Inhibition Triggers Viral Oncoprotein Degradation via Autophagy-Lysosomal Pathway

New Approaches to Targeting B Cells for Myasthenia Gravis Therapy

A Single Membrane Protein Required for Atrial Secretory Granule Formation

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