Activation of the membrane-bound Nrf1 transcription factor by USP19, a ubiquitin-specific protease C-terminally anchored in the endoplasmic reticulum

Hu, Shaofan; Xiang, Yuancai; Qiu, Lu; Wang, Meng; Zhang, Yiguo

doi:10.1016/j.bbamcr.2022.119299

Cited by 11 publications

(11 citation statements)

References 42 publications

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“…In this family, Nrf1 can activate transcriptional expression of Herpud1 (homocysteine-inducible ER-resident protein with ubiquitin-like domain 1, also called Herp1, that is involved in both UPR and ERAD) driven by its ARE battery, and the resulting ubiquitin complex is transferred to the proteasome in order to promote the unfolded and misfolded protein degradation, thereby preventing or alleviating the ER-overloaded stress [ 42 ]. This notion is supported by experimental evidence that endogenous ER stress signaling to activate UPR occurs in steatotic hepatocytes with homozygous knockout of Nrf1 −/− , but not of Nrf2 −/− [ 23 ]. Therefore, it is inferable that Nrf1 plays an important role in maintaining the ER redox homeostasis, particularly upon sensing intracellular protein, lipid, glucose and redox challenges.…”

Section: Discussionmentioning

confidence: 88%

“…Our previous work demonstrated differential and integral contributions of Nrf1 and Nrf2 to coordinately mediating distinct responsive gene expression profiles to the ER stressor tunicamycin (TU) [ 20 ] and pro-oxidative stressor tert -butylhydroquinone ( t BHQ) [ 22 ]. Recently, Nrf1, rather than Nrf2, was further identified as an indispensable redox-determining factor for mitochondrial homeostasis, in addition to the ER-associated proteostasis, by integrating multi-hierarchical responsive signaling pathways through nuclear respiratory gene controls towards mitochondrially located gene regulatory networks [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Distinct Roles of Nrf1 and Nrf2 in Monitoring the Reductive Stress Response to Dithiothreitol (DTT)

et al. 2022

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Transcription factor Nrf2 (nuclear factor, erythroid 2-like 2, encoded by Nfe2l2) has been accepted as a key player in redox regulatory responses to oxidative or reductive stresses. However, relatively little is known about the potential role of Nrf1 (nuclear factor, erythroid 2-like 1, encoded by Nfe2l1) in the redox responses, particularly to reductive stress, although this ‘fossil-like’ factor is indispensable for cell homeostasis and organ integrity during the life process. Herein, we examine distinct roles of Nrf1 and Nrf2 in monitoring the defense response to 1,4–dithiothreitol (DTT, serving as a reductive stressor), concomitantly with unfolded protein response being induced by this chemical (also defined as an endoplasmic reticulum stressor). The results revealed that intracellular reactive oxygen species (ROS) were modestly increased in DTT-treated wild-type (WT) and Nrf1α−/− cell lines, but almost unaltered in Nrf2−/−ΔTA or caNrf2ΔN cell lines (with a genetic loss of transactivation or N-terminal Keap1-binding domains, respectively). This chemical treatment also enabled the rate of oxidized to reduced glutathione (i.e., GSSG to GSH) to be amplified in WT and Nrf2−/−ΔTA cells, but diminished in Nrf1α−/− cells, along with to or less extents changes in caNrf2ΔN cells. Consequently, Nrf1α−/−, but not Nrf2−/−ΔTA or caNrf2ΔN, cell viability was reinforced by DTT against its cytotoxicity, as accompanied by decreased apoptosis. Further experiments unraveled that Nrf1 and Nrf2 differentially, and also synergistically, regulated DTT-inducible expression of critical genes for defending against redox stress and endoplasmic reticulum stress. In addition, we also identified that Cys342 and Cys640 of Nrf1 (as redox-sensing sites within its N-glycodomain and DNA-binding domain, respectively) are required for its protein stability and transcription activity.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Distinct Roles of Nrf1 and Nrf2 in Monitoring the Reductive Stress Response to Dithiothreitol (DTT)

et al. 2022

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“…In this family, Nrf1 can activate transcriptional expression of Herpud1 (homocysteine-inducible ER-resident protein with ubiquitin-like domain 1, also called Herp1, that is involved in both UPR and ERAD) driven by its ARE battery, and the resulting ubiquitin complex is transferred to the proteasome in order to promote the unfolded and misfolded protein degradation, thereby preventing or alleviating the ER-overloaded stress (40). This notion is supported by experimental evidence that endogenous ER stress signaling to activate UPR occur in the steatotic hepatocytes cells with homozygous knockout of Nrf1 -∕-, but not of Nrf2 -∕- (21). Therefore, it is inferable that Nrf1 plays an important role in maintaining the ER redox homeostasis, particularly upon sensing intracellular protein, lipid, glucose and redox challenges.…”

Section: Discussionmentioning

confidence: 96%

“…Our previous work demonstrated differential and integral contributions of Nrf1 and Nrf2 to coordinately mediating distinct responsive gene expression profiles to the ER stressor tunicamycin (TU) (19) and pro-oxidative stressor tert -butylhydroquinone ( t BHQ)(20). Recently, Nrf1, rather than Nrf2, is further identified as an indispensable redox-determining factor for mitochondrial homeostasis, in addition to the ER-associated proteostasis, by integrating multi-hierarchical responsive signaling pathways through those nuclearly-located respiratory gene controls towards mitochondrially-located gene regulatory networks (21). Herein, we found distinctive roles of Nrf1 and Nrf2 in synergistically monitoring the defense response to DTT as a reductive stressor, concomitantly with unfolded protein response being induced by this chemical (also serving as an ER stressor).…”

Section: Introductionmentioning

confidence: 99%

Distinct roles of Nrf1 and Nrf2 in monitoring the reductive stress response to dithiothreitol (DTT)

Wufuer

Fan

Yuan

et al. 2022

Preprint

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Transcription factor Nrf2 (nuclear factor, erythroid 2-like 2, encoded by Nfe2l2) has been accepted as a key player in redox regulatory responses to oxidative or reductive stresses. However, it is less or not known about the potential role for Nrf1 (nuclear factor, erythroid 2-like 1, encoded by Nfe2l1) in the redox responses, particularly to reductive stress, albeit this fossil-like factor is indispensable for cell homeostasis and organ integrity during life process. Here, we examine distinct roles of Nrf1 and Nrf2 in monitoring the defense response to 1,4-dithiothreitol (DTT, serving as a reductive stressor), concomitantly with unfolded protein response being induced by this chemical (also as an endoplasmic reticulum stressor). The results revealed that intracellular reactive oxygen species (ROS) were modestly increased in DTT-treated wild-type (WT) and Nrf1α-∕- cell lines, but almost unaltered in Nrf2-∕-ΔTA or caNrf2ΔN cell lines (with a genetic loss of its transactivation or N-terminal Keap1-binding domains, respectively). This chemical treatment also enabled the rate of oxidized to reduced glutathione (i.e., GSSG to GSH) to be amplified in WT and Nrf2-∕-ΔTA cells, but diminished in Nrf1α-∕- cells, along with no changes in caNrf2ΔN cells. Consequently, Nrf1α-∕-, but not Nrf2-∕-ΔTA or caNrf2ΔN, cell viability was reinforced by DTT against its cytotoxicity, as accompanied by decreased apoptosis. Further experiments unraveled that Nrf1 and Nrf2 differentially, and also synergistically, regulated DTT-inducible expression of critical genes for defending redox stress and endoplasmic reticulum stress. In addition, we have also identified that Cys342 and Cys640 of Nrf1 (as redox-sensing sites within its N-glycodomain and DNA-binding domain, respectively) are required for its protein stability and transcription activity.

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“…The knockdown of Synoviolin negated such a rescue , whereas the upregulation of Synoviolin by Icariin was further negated by NFE2L1 knockdown. In turn, the proper turnover of the ER-localized NFE2L1 per se is also tightly regulated by Synoviolin/HRD1-mediated ubiquitination of this CNC-bZIP protein, targeting it to an ERAD-dependent disposal system [ 8 ], but rather finely monitored by USP19-mediated deubiquitination to salvage this CNC-bZIP factor via the ERAD-regulatory feedback loop [ 49 ]. Moreover, NFE2L1 is also essentially required to mediate the UPR mitochondrial stress (i.e., UPR Mito ) and determines mitochondrial redox homeostasis during healthy living [ 50 ].…”

Section: Nfe2l1 Governs Vital Molecular Pathways In Neuronal Cellsmentioning

confidence: 99%

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases

Łuczyńska,

Zhang,

Pietras

et al. 2024

Redox Biology

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Activation of the membrane-bound Nrf1 transcription factor by USP19, a ubiquitin-specific protease C-terminally anchored in the endoplasmic reticulum

Cited by 11 publications

References 42 publications

Distinct Roles of Nrf1 and Nrf2 in Monitoring the Reductive Stress Response to Dithiothreitol (DTT)

Distinct Roles of Nrf1 and Nrf2 in Monitoring the Reductive Stress Response to Dithiothreitol (DTT)

Distinct roles of Nrf1 and Nrf2 in monitoring the reductive stress response to dithiothreitol (DTT)

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases

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