Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy

2013 ◽  
Vol 70 (24) ◽  
pp. 4681-4694 ◽  
Author(s):  
Hadi Digaleh ◽  
Mahmoud Kiaei ◽  
Fariba Khodagholi
2005 ◽  
Vol preprint (2007) ◽  
pp. 1
Author(s):  
Marina Shenkman ◽  
Sandra Tolchinsky ◽  
Gerardo Lederkremer

2016 ◽  
Vol 311 (5) ◽  
pp. F1035-F1046 ◽  
Author(s):  
Kapil Sareen-Khanna ◽  
Joan Papillon ◽  
Simon S. Wing ◽  
Andrey V. Cybulsky

Kidney cell injury may be associated with protein misfolding and induction of endoplasmic reticulum (ER) stress. Examples include complement-induced glomerular epithelial cell (GEC)/podocyte injury in membranous nephropathy and ischemia-reperfusion injury. Renal cell injury can also result from mutations in integral proteins, which lead to their misfolding and accumulation. Certain nephrin missense mutants misfold, accumulate in the ER, and induce ER stress. We examined if enhancement of ubiquitin-proteasome system function may facilitate proteostasis and confer protection against injury. Ubiquitin-specific protease 14 (Usp14) is reported to retard proteasomal protein degradation. Thus inhibition of Usp14 may enhance degradation of misfolded proteins and attenuate cell injury. In GEC, the reporter proteins GFPu (a “misfolded” protein) and CD3δ (an ER-associated degradation substrate) undergo time-dependent proteasomal degradation. Complement did not affect degradation of CD3δ-yellow fluorescent protein (YFP), but accelerated degradation of GFPu, and the Usp14-directed inhibitor IU1 further accelerated this degradation. Conversely, overexpression of Usp14 reduced degradation of GFPu and CD3δ-YFP. In 293T cells, IU1 did not enhance degradation of disease-associated nephrin missense mutants I171N and S724C, whereas overexpression of Usp14 reduced degradation. IU1 was cytoprotective after injury induced by the ER stressor tunicamycin and in vitro ischemia-reperfusion, but did not affect complement-induced cytotoxicity. In conclusion, Usp14 controls proteasomal degradation of some misfolded proteins. In addition, a Usp14-directed inhibitor reduces cytotoxicity in the context of global protein misfolding during certain types of renal cell injury.


eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Antonio Galeone ◽  
Joshua M Adams ◽  
Shinya Matsuda ◽  
Maximiliano F Presa ◽  
Ashutosh Pandey ◽  
...  

During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzyme N-glycanase 1 (NGLY1) is proposed to remove N-glycans from misfolded N-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulates Drosophila BMP signaling in a tissue-specific manner (Galeone et al., 2017). Here, we establish the Drosophila Dpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress and prompts the ER recruitment of NGLY1. The ER-associated NGLY1 then deglycosylates misfolded BMP4 molecules to promote their retrotranslocation and proteasomal degradation, thereby allowing properly-folded BMP4 molecules to proceed through the secretory pathway and activate signaling in other cells. Our study redefines the role of NGLY1 during ERAD and suggests that impaired BMP4 signaling might underlie some of the NGLY1 deficiency patient phenotypes.


Phytomedicine ◽  
2021 ◽  
Vol 92 ◽  
pp. 153763
Author(s):  
Hyeongjoo Oh ◽  
Min-Kyung Kang ◽  
Sin-Hye Park ◽  
Dong Yeon Kim ◽  
Soo-Il Kim ◽  
...  

2013 ◽  
Vol 8 (S 01) ◽  
Author(s):  
S Behrendt ◽  
D Löffler ◽  
R Tauscher ◽  
A Körner

2013 ◽  
Vol 8 (S 01) ◽  
Author(s):  
D Sommerweiss ◽  
T Gorski ◽  
S Laue ◽  
S Schuster ◽  
A Garten ◽  
...  
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