Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans; pleiotrophy, aging, glutathione, and interactions with other longevity pathways

Tang, Lanlan; Choe, Keith P.

doi:10.1016/j.mad.2015.06.001

Cited by 54 publications

(61 citation statements)

References 59 publications

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“…In C. elegans, the WD40-repeat protein WDR-23 acts as a principal suppressor of SKN-1 activity (Choe et al, 2009). As shown previously (Tang and Choe, 2015), SKN-1 activity is lowest in wild-type N2 worms, higher in wdr-23(k1002) mutants with a wdr-23 loss-of-function allele, higher still in skn-1(k1023) mutants with a skn-1 gain-offunction allele, and highest in wdr-23(tm1817) mutants with a wdr-23 deletion allele (Fig. 1).…”

Section: Heat Stress and Oxidative Stress Synergistically Decrease Susupporting

confidence: 60%

“…Additional mechanisms could include disruption of the redox signaling that is required for some protein chaperones (Jang et al, 2004), and competition between the OxSR and the HSR for ATP and other cellular resources necessary for gene expression and protein translation. The loss of wdr-23 increases longevity and resistance to oxidative stress, but decreases growth and reproduction in a SKN-1-dependent manner (Tang and Choe, 2015). The fact that stress resistance and longevity necessitate trade-offs with development and reproduction is well known (Flatt, 2011;Jenkins et al, 2004).…”

Section: Skn-1 Activation Is Detrimental To Survival Under Heat Stressmentioning

confidence: 99%

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Inhibition of the oxidative stress response by heat stress inCaenorhabditis elegans

Crombie

Tang

Choe

et al. 2016

Journal of Experimental Biology

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It has long been recognized that simultaneous exposure to heat stress and oxidative stress shows a synergistic interaction that reduces organismal fitness, but relatively little is known about the mechanisms underlying this interaction. We investigated the role of molecular stress responses in driving this synergistic interaction using the nematode Caenorhabditis elegans. To induce oxidative stress, we used the pro-oxidant compounds acrylamide, paraquat and juglone. As expected, we found that heat stress and oxidative stress interact synergistically to reduce survival. Compared with exposure to each stressor alone, during simultaneous sublethal exposure to heat stress and oxidative stress the normal induction of key oxidative-stress response (OxSR) genes was generally inhibited, whereas the induction of key heat-shock response (HSR) genes was not. Genetically activating the SKN-1-dependent OxSR increased a marker for protein aggregation and decreased whole-worm survival during heat stress alone, with the latter being independent of HSF-1. In contrast, compared with wild-type worms, inactivating the HSR by HSF-1 knockdown, which would be expected to decrease basal heat shock protein expression, increased survival during oxidative stress alone. Taken together, these data suggest that, in C. elegans, the HSR and OxSR cannot be simultaneously activated to the same extent that each can be activated during a single stressor exposure. We conclude that the observed synergistic reduction in survival during combined exposure to heat stress and oxidative stress is due, at least in part, to inhibition of the OxSR during activation of the HSR.

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Section: Heat Stress and Oxidative Stress Synergistically Decrease Susupporting

confidence: 60%

Section: Skn-1 Activation Is Detrimental To Survival Under Heat Stressmentioning

confidence: 99%

Inhibition of the oxidative stress response by heat stress inCaenorhabditis elegans

Crombie

Tang

Choe

et al. 2016

Journal of Experimental Biology

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“…gst-4 encodes a glutathione S-transferase implicated in oxidative stress responses and xenobiotic detoxification. gst-4 p ::gfp is induced in a skn-1dependent manner in response to a number of stimuli including proteasome inhibition and oxidative stress (Paek et al, 2012;Pang et al, 2014;Tang and Choe, 2015). The length and sequence of SKN-1 also affects its ability to regulate gst-4 p ::gfp, but in a manner distinct from rpt-3 p ::gfp ( Figure 3B).…”

Section: Conversion Of Glycosylated Asparagine Residues Of Skn-1a To mentioning

confidence: 98%

Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression

Lehrbach

Breen

Ruvkun

2019

Cell

104

120

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Graphical Abstract Highlights d PNGase edits glycosylated Asn residues of the SKN-1A transcription factor to Asp d These edits are required for SKN-1A to regulate proteasome subunit genes d Sequence-edited SKN-1A enhances proteostasis d Edits cause ER-targeted and cytosolic SKN-1 isoforms to regulate distinct genes SUMMARYThe proteasome mediates selective protein degradation and is dynamically regulated in response to proteotoxic challenges. SKN-1A/Nrf1, an endoplasmic reticulum (ER)-associated transcription factor that undergoes N-linked glycosylation, serves as a sensor of proteasome dysfunction and triggers compensatory upregulation of proteasome subunit genes. Here, we show that the PNG-1/NGLY1 peptide:N-glycanase edits the sequence of SKN-1A protein by converting particular N-glycosylated asparagine residues to aspartic acid. Genetically introducing aspartates at these N-glycosylation sites bypasses the requirement for PNG-1/NGLY1, showing that protein sequence editing rather than deglycosylation is key to SKN-1A function. This pathway is required to maintain sufficient proteasome expression and activity, and SKN-1A hyperactivation confers resistance to the proteotoxicity of human amyloid beta peptide. Deglycosylationdependent protein sequence editing explains how ER-associated and cytosolic isoforms of SKN-1 perform distinct cytoprotective functions corresponding to those of mammalian Nrf1 and Nrf2. Thus, we uncover an unexpected mechanism by which N-linked glycosylation regulates protein function and proteostasis.

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“…elegans , a mechanistically similar pathway negatively regulates the abundance of SKN-1, the worm equivalent of NRF2, but via the action of WDR-23[21, 22] and the CUL-4 E3 ubiquitin ligase, not CUL-3[23]. WDR-23 is a WD40-repeat protein, containing seven repeats of the tryptophan aspartic acid (WD) containing motif.…”

Section: Introductionmentioning

confidence: 99%

WDR23 regulates NRF2 independently of KEAP1

Spatola

Curran

2017

PLoS Genet

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Cellular adaptation to stress is essential to ensure organismal survival. NRF2/NFE2L2 is a key determinant of xenobiotic stress responses, and loss of negative regulation by the KEAP1-CUL3 proteasome system is implicated in several chemo- and radiation-resistant cancers. Advantageously using C. elegans alongside human cell culture models, we establish a new WDR23-DDB1-CUL4 regulatory axis for NRF2 activity that operates independently of the canonical KEAP1-CUL3 system. WDR23 binds the DIDLID sequence within the Neh2 domain of NRF2 to regulate its stability; this regulation is not dependent on the KEAP1-binding DLG or ETGE motifs. The C-terminal domain of WDR23 is highly conserved and involved in regulation of NRF2 by the DDB1-CUL4 complex. The addition of WDR23 increases cellular sensitivity to cytotoxic chemotherapeutic drugs and suppresses NRF2 in KEAP1-negative cancer cell lines. Together, our results identify WDR23 as an alternative regulator of NRF2 proteostasis and uncover a cellular pathway that regulates NRF2 activity and capacity for cytoprotection independently of KEAP1.

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Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans; pleiotrophy, aging, glutathione, and interactions with other longevity pathways

Cited by 54 publications

References 59 publications

Inhibition of the oxidative stress response by heat stress inCaenorhabditis elegans

Inhibition of the oxidative stress response by heat stress inCaenorhabditis elegans

Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression

WDR23 regulates NRF2 independently of KEAP1

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