The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction

Koizumi, Shun; Irie, Taro; Hirayama, Shoshiro; Sakurai, Yoshihiko; Yashiroda, Hideki; Naguro, Isao; Ichijo, Hidenori; Hamazaki, Jun; Murata, Shigeo

doi:10.7554/elife.18357

Cited by 158 publications

(202 citation statements)

References 16 publications

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“…5g). To further test the importance of Nrf1-mediated proteasome production as a pro-survival mechanism that is inhibited by LU-102 co-treatment, we knocked down DDI2, an aspartyl protease involved in cleavage of Nrf1 to its active form (Koizumi et al, 2016; Lehrbach and Ruvkun, 2016). We found that knocking down DDI2 in SUM149 cells with siRNA also caused a significant increase in apoptosis upon Cfz-treatment, while there was no change in cells treated with Cfz+LU-102 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of Nrf1 upon proteasome inhibition requires the protease DDI2 (Koizumi et al, 2016; Lehrbach and Ruvkun, 2016; Sha and Goldberg, 2016), which cleaves the ER-bound precursor of Nrf1 to a smaller form. However, in order for the cleaved Nrf1 to be active, it must also remain soluble.…”

Section: Discussionmentioning

confidence: 99%

“…Complexes were added dropwise to cells at the time of plating, and cells were allowed to attach for 24 h before starting treatment. siRNAs were obtained from GE Dharmacon: NFE2L1 (L-019733-00-0010); non-targeting siRNA #1 (D-001810-01-05); and a custom DDI2 siRNA (Sense: 5′ GCCAAGUAGUGAUGCUUUA 3′ (Koizumi et al, 2016)).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation

Weyburne

Wilkins

Sha

et al. 2017

Cell Chemical Biology

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Summary The proteasome inhibitors Carfilzomib (Cfz) and Bortezomib (Btz) are used successfully to treat MM, but have not shown clinical efficacy in solid tumors. Here we show that clinically achievable inhibition of the β5 site of the proteasome by Cfz and Btz does not result in loss of viability of triple-negative breast cancer cell lines. We use site-specific inhibitors and CRISPR-mediated genetic inactivation of β1 and β2 to demonstrate that inhibiting a second site of the proteasome, particularly the β2 site, sensitizes cell lines to Btz and Cfz in vitro and in vivo. Inhibiting both β5 and β2 suppresses production of the soluble, active form of the transcription factor Nrf1 and prevents the recovery of proteasome activity through induction of new proteasomes. These findings provide a strong rationale for the development of dual β5 and β2 inhibitors for the treatment of solid tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation

Weyburne

Wilkins

Sha

et al. 2017

Cell Chemical Biology

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“…This short-lived protein is expressed as a larger precursor fixed to the ER. When proteasomes are inhibited, Nrf1 is cleaved by the endoprotease Ddi2 (Koizumi et al, 2016; Lehrbach and Ruvkun, 2016; Sha and Goldberg, 2016). The released fragment enters the nucleus and induces expression of all 26S subunits, p97, and its cofactors.…”

Section: Alterations Of Proteasome Activity Upon Phosphorylation or Pmentioning

confidence: 99%

The Logic of the 26S Proteasome

Collins

Goldberg

2017

Cell

754

697

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“…This protein is an ER-targeted glycoprotein (Wang and Chan 2006;Zhang et al 2007) that is constitutively turned over by the proteasome in a Cdc48-dependent fashion (Radhakrishnan et al 2014). When proteasome function is compromised, Nrf1 levels accumulate and the protein is proteolytically cleaved by the proteasome itself (Sha and Goldberg 2014), or by an aspartyl protease (Koizumi et al 2016;Lehrbach and Ruvkun 2016), prior to activating proteasome gene expression…”

Section: The Role Of Subunit Expression Stoichiometry In Assembly Effmentioning

confidence: 99%

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

2017

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BACKGROUND:The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly. OBJECTIVE:In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells. METHODS:A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review. RESULTS:Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones. CONCLUSION:Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

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The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction

Cited by 158 publications

References 16 publications

Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation

Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation

The Logic of the 26S Proteasome

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

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