Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized Proteins<i>In Vivo</i>

Manohar, Sandhya; Jacob, Samson T.; Wang, Jade; Wiechecki, Keira A; Koh, Hiromi W. L.; Simões, Vanessa; Choi, Hyungwon; Vogel, Christine; Silva, Gustavo M.

doi:10.1089/ars.2019.7826

Cited by 30 publications

(28 citation statements)

References 74 publications

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“…For example, Cyclin B1 is degraded by proteasome into multiple short chains to regulate cell cycle [15,16]. Oxidized histone protein Htb2, a core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chainenhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22].…”

Section: The Ubiquitin-proteasome System Is Essential For the Maintenmentioning

confidence: 99%

“…This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22].…”

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Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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Section: The Ubiquitin-proteasome System Is Essential For the Maintenmentioning

confidence: 99%

mentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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“…ROS are important signaling molecules but can also damage cellular infrastructure due to their reactive nature [158]. During oxidative stress, eukaryotic cells accumulate large amounts of ubiquitinated proteins [65,159], and much of the earlier research was focused on the degradation role of ubiquitin in the removal of oxidatively damaged proteins [159][160][161][162][163]. Although protein degradation is an important mechanism to control ribosome abundance (discussed in Section 3), more recent work has focused on the non-degradative role ubiquitin plays in translational regulation under oxidative stress [50,164,165].…”

Section: Role Of Ubiquitin In Oxidative Stress Responsementioning

confidence: 99%

“…ROS-driven modification of ribosomal proteins and rRNA alters the function and efficiency of the ribosomes, as extensively reviewed by Shcherbik and Pestov [165]. These modifications include the K48 polyubiquitination of ribosomal proteins, which leads to their degradation by the canonical UPS [163]. In addition to causing damage, ROS can also act as a signaling molecule, interacting with regulatory enzymes, thereby activating adaptive cellular responses [169].…”

Section: Translational Control Under Oxidative Stressmentioning

confidence: 99%

Expanding Role of Ubiquitin in Translational Control

Dougherty

Maduka

Inada

et al. 2020

IJMS

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The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.Int. J. Mol. Sci. 2020, 21, 1151 2 of 24 initiation, elongation, and termination, with each being fundamental processes conserved across all organisms [20][21][22]. These steps require the proper binding of both RNA and protein factors, and regulation is often facilitated by the alteration of these binding patterns. As ribosomes are highly abundant and responsible for all protein synthesis within the cell, even minor changes to binding patterns could have a large impact on global protein production and cellular health, depending on which steps of translation are altered. Mutations and dysregulation of translational control can lead to a variety of diseases such as cancer, neurological disorders, bone marrow dysfunction and immunodeficiency, among others [23]. As translation is a core process in maintaining cellular function and health, dysfunctional regulation can have devastating results for the cell.Translational control does not occur in a universal manner across a single cell, but varies based on ribosomal subpopulations, with functions specific to cellular localization, transcript targeting, and signaling pathways [24,25]. These subpopulations are distinguishable by RNA and ribosomal protein composition [26,27], binding factors [28], intracellular localization [29,30], and post-translational modifications (PTM) [31]. These subpopulations have a differential capacity to bind and interact with both mRNA and protein factors required for active transla...

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“…Oxidized proteins form a class of intrinsically disordered proteins, which can be degraded by the 20S proteasome without ubiquitination. In addition, exposure to oxidative stress results in global ubiquitination of oxidized proteins with Lys48-linked polyubiquitin (polyUb) chains and their subsequent degradation by the 26S proteasome [9]. Notably, non-degradable Lys63-polyUb chains also appeared to have a regulatory role during the early phase of the oxidative stress response [10].…”

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confidence: 99%

Reduced chronic restraint stress in mice overexpressing hyperactive proteasomes in the forebrain

Kim

Yun

et al. 2020

Mol Brain

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While chronic restraint stress (CRS) results in depression-like behaviors possibly through oxidative stress in the brain, its molecular etiology and the development of therapeutic strategies remain elusive. Since oxidized proteins can be targeted by the ubiquitin-proteasome system, we investigated whether increased proteasome activity might affect the stress response in mice. Transgenic mice, expressing the N-terminally deleted version of α3 subunit (α3ΔN) of the proteasome, which has been shown to generate open-gated mutant proteasomes, in the forebrain were viable and fertile, but showed higher proteasome activity. After being challenged with CRS for 14 d, the mutant mice with hyperactive proteasomes showed significantly less immobility time in the forced swimming test compared with their wild-type littermates, suggesting that the α3ΔN transgenic mice are resistant to CRS. The accumulation of ER stress markers, such as polyubiquitin conjugates and phospho-IRE1α, was also significantly delayed in the hippocampus of the mutants. Notably, α3ΔN mice exhibited little deficits in other behavioral tasks, suggesting that stress resilience is likely due to the degradation of misfolded proteins by the open-gated proteasomes. These data strongly indicate that not only is the proteasome a critical modulator of stress response in vivo but also a possible therapeutic target for reducing chronic stress.

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Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized ProteinsIn Vivo

Cited by 30 publications

References 74 publications

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Expanding Role of Ubiquitin in Translational Control

Reduced chronic restraint stress in mice overexpressing hyperactive proteasomes in the forebrain

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