Dynamic Regulation of Proteasome Expression

Motosugi, Ryo; Murata, Shigeo

doi:10.3389/fmolb.2019.00030

Cited by 47 publications

(33 citation statements)

References 72 publications

(75 reference statements)

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“…The RING finger subclass is subdivided into two subfamilies: Cullin-containing RING-finger ligases (CRLs) and those in which the RING-finger and substrate binding domains are contained on the same polypeptide. Regardless of the well-known role of E3 ligases on proteasome substrates, it is also accepted that they have a role in the ubiquitylation of a variety of proteasome subunits [80,81,82,83]. For instance, the E3 RING ligase Not4 triggers direct ubiquitylation of the Rpt5 subunit, playing a crucial function in 26S proteasome assembly [84].…”

Section: Proteasome Compositionmentioning

confidence: 99%

Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

Albornoz

Bustamante

Soza

et al. 2019

IJMS

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Proteasome inhibitors have been actively tested as potential anticancer drugs and in the treatment of inflammatory and autoimmune diseases. Unfortunately, cells adapt to survive in the presence of proteasome inhibitors activating a variety of cell responses that explain why these therapies have not fulfilled their expected results. In addition, all proteasome inhibitors tested and approved by the FDA have caused a variety of side effects in humans. Here, we describe the different types of proteasome complexes found within cells and the variety of regulators proteins that can modulate their activities, including those that are upregulated in the context of inflammatory processes. We also summarize the adaptive cellular responses activated during proteasome inhibition with special emphasis on the activation of the Autophagic-Lysosomal Pathway (ALP), proteaphagy, p62/SQSTM1 enriched-inclusion bodies, and proteasome biogenesis dependent on Nrf1 and Nrf2 transcription factors. Moreover, we discuss the role of IRE1 and PERK sensors in ALP activation during ER stress and the involvement of two deubiquitinases, Rpn11 and USP14, in these processes. Finally, we discuss the aspects that should be currently considered in the development of novel strategies that use proteasome activity as a therapeutic target for the treatment of human diseases.

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Section: Proteasome Compositionmentioning

confidence: 99%

Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

Albornoz

Bustamante

Soza

et al. 2019

IJMS

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“…Recent results in human cells point to a role for DDI proteins in suppressing replication stress through an effect on the stability of replication termination factor 2 (RTF2) ( Kottemann et al., 2018 ), but more is known about the effect of DDI2 on transcription factor NRF1 (NFE2L1) ( Motosugi and Murata, 2019 ). This protein is normally primarily associated with the endoplasmic reticulum (ER), but upon proteasome inhibition, protein processing allows NRF1 to enter the nucleus and upregulate a subset of genes, including those encoding proteasome subunits ( Radhakrishnan et al., 2010 , Radhakrishnan et al., 2014 , Sha and Goldberg, 2014 , Vangala et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…We now investigated the hypothesis that DDI2 recognizes ubiquitylated proteins and then sometimes cleaves the ubiquitylated protein itself. Upon proteasome inhibition, DDI2 -dependent processing allows NRF1 to enter the nucleus and upregulate a subset of genes, including proteasome genes (reviewed by Motosugi and Murata, 2019 ), but whether DDI2 is directly responsible was unclear. Indeed, previous attempts at cleaving NRF1 in vitro were unsuccessful ( Koizumi et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

DDI2 Is a Ubiquitin-Directed Endoprotease Responsible for Cleavage of Transcription Factor NRF1

et al. 2020

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Summary The Ddi1/DDI2 proteins are ubiquitin shuttling factors, implicated in a variety of cellular functions. In addition to ubiquitin-binding and ubiquitin-like domains, they contain a conserved region with similarity to retroviral proteases, but whether and how DDI2 functions as a protease has remained unknown. Here, we show that DDI2 knockout cells are sensitive to proteasome inhibition and accumulate high-molecular weight, ubiquitylated proteins that are poorly degraded by the proteasome. These proteins are targets for the protease activity of purified DDI2. No evidence for DDI2 acting as a de-ubiquitylating enzyme was uncovered, which could suggest that it cleaves the ubiquitylated protein itself. In support of this idea, cleavage of transcription factor NRF1 is known to require DDI2 activity in vivo . We show that DDI2 is indeed capable of cleaving NRF1 in vitro but only when NRF1 protein is highly poly-ubiquitylated. Together, these data suggest that DDI2 is a ubiquitin-directed endoprotease.

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“…The expression of the proteasome is dynamically induced in response to specific cellular environments (Motosugi & Murata, ). For example, proteasome impairment, feeding and growth factors induce proteasome expression in a Nrf1‐dependent manner (Radhakrishnan et al, ; Zhang et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…These observations raise the possibility that defects in TCR-mediated induction of the proteasome underlie T-cell senescence. The expression of the proteasome is dynamically induced in response to specific cellular environments (Motosugi & Murata, 2019). For example, proteasome impairment, feeding and growth factors induce proteasome expression in a Nrf1dependent manner (Radhakrishnan et al, 2010;Zhang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Defective induction of the proteasome associated with T‐cell receptor signaling underlies T‐cell senescence

et al. 2019

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The proteasome degradation machinery is essential for a variety of cellular processes including senescence and T‐cell immunity. Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4+ T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4+ T cells upon T‐cell receptor (TCR) stimulation underlie T‐cell senescence. Proteasome dysfunction promotes senescence‐associated phenotypes, including defective proliferation, cytokine production and increased levels of PD‐1+ CD44High CD4+ T cells. Proteasome induction by TCR signaling via MEK‐, IKK‐ and calcineurin‐dependent pathways is attenuated with age and decreased in PD‐1+ CD44High CD4+ T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4+ T‐cell senescence.

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Dynamic Regulation of Proteasome Expression

Cited by 47 publications

References 72 publications

Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

DDI2 Is a Ubiquitin-Directed Endoprotease Responsible for Cleavage of Transcription Factor NRF1

Defective induction of the proteasome associated with T‐cell receptor signaling underlies T‐cell senescence

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