scholarly journals Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1

2016 ◽  
Author(s):  
Nicolas J. Lehrbach ◽  
Gary Ruvkun
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Proteasome Inhibitor ◽  
Cellular Function ◽  
Aspartic Protease ◽  
Protein Homeostasis ◽  
Genetic Analyses ◽  
Proteasome Subunit ◽  
C Elegans

ABSTRACTProteasomes are essential for protein homeostasis in eukaryotes. To preserve cellular function, transcription of proteasome subunit genes is induced in response to proteasome dysfunction caused by pathogen attacks or proteasome inhibitor drugs. In Caenorhabditis elegans, this response requires SKN-1, a transcription factor related to mammalian Nrf1/2. Here, we use comprehensive genetic analyses to identify the pathway required for C. elegans to detect proteasome dysfunction and activate SKN-1. Genes required for SKN-1 activation encode regulators of ER traffic, a peptide N-glycanase, and DDI-1, a conserved aspartic protease. DDI-1 expression is induced by proteasome dysfunction, and we show that DDI-1 is required to cleave and activate an ER-associated isoform of SKN-1. Mammalian Nrf1 is also ER-associated and subject to proteolytic cleavage, suggesting a conserved mechanism of proteasome surveillance. Targeting mammalian DDI1 protease could mitigate effects of proteasome dysfunction in aging and protein aggregation disorders, or increase effectiveness of proteasome inhibitor cancer chemotherapies.

scholarly journals Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Nicolas J Lehrbach ◽  
Gary Ruvkun
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Proteasome Inhibitor ◽  
Cellular Function ◽  
Aspartic Protease ◽  
Protein Homeostasis ◽  
Genetic Analyses ◽  
Proteasome Subunit ◽  
C Elegans

Proteasomes are essential for protein homeostasis in eukaryotes. To preserve cellular function, transcription of proteasome subunit genes is induced in response to proteasome dysfunction caused by pathogen attacks or proteasome inhibitor drugs. In Caenorhabditis elegans, this response requires SKN-1, a transcription factor related to mammalian Nrf1/2. Here, we use comprehensive genetic analyses to identify the pathway required for C. elegans to detect proteasome dysfunction and activate SKN-1. Genes required for SKN-1 activation encode regulators of ER traffic, a peptide N-glycanase, and DDI-1, a conserved aspartic protease. DDI-1 expression is induced by proteasome dysfunction, and we show that DDI-1 is required to cleave and activate an ER-associated isoform of SKN-1. Mammalian Nrf1 is also ER-associated and subject to proteolytic cleavage, suggesting a conserved mechanism of proteasome surveillance. Targeting mammalian DDI1 protease could mitigate effects of proteasome dysfunction in aging and protein aggregation disorders, or increase effectiveness of proteasome inhibitor cancer chemotherapies.

scholarly journals Temporal Requirements of SKN-1/NRF as a Regulator of Lifespan and Proteostasis in Caenorhabditis elegans

2020 ◽  
Author(s):  
Danielle Grushko ◽  
Amir Levine ◽  
Hana Boocholez ◽  
Ehud Cohen
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Caenorhabditis Elegans ◽  
Stress Resistance ◽  
Healthy Aging ◽  
Early Adulthood ◽  
Protein Homeostasis ◽  
Heat Shock Factor 1 ◽  
C Elegans ◽  
Extended Lifespan

AbstractLowering the activity of the Insulin/IGF-1 Signaling (IIS) cascade results in elevated stress resistance, enhanced protein homeostasis (proteostasis) and extended lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), the longevity phenotype that stems from IIS reduction is entirely dependent upon the activities of a subset of transcription factors including the Forkhead factor DAF-16/FOXO (DAF-16), Heat Shock Factor-1 (HSF-1), SKiNhead/Nrf (SKN-1) and ParaQuat Methylviologen responsive (PQM-1). While DAF-16 determines lifespan exclusively during early adulthood and governs proteostasis in early adulthood and midlife, HSF-1 executes these functions foremost during development. Despite the central roles of SKN-1 as a regulator of lifespan and proteostasis, the temporal requirements of this transcription factor were unknown. Here we employed conditional knockdown techniques and discovered that in C. elegans, SKN-1 is primarily important for longevity and proteostasis during late larval development through early adulthood. Our findings indicate that events that occur during late larval developmental through early adulthood affect lifespan and proteostasis and suggest that subsequent to HSF-1, SKN-1 sets the conditions, partially overlapping temporally with DAF-16, that enable IIS reduction to promote longevity and proteostasis. Our findings raise the intriguing possibility that HSF-1, SKN-1 and DAF-16 function in a coordinated and sequential manner to promote healthy aging.

scholarly journals Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mercedes M. Pérez-Jiménez ◽  
José M. Monje-Moreno ◽  
Ana María Brokate-Llanos ◽  
Mónica Venegas-Calerón ◽  
Alicia Sánchez-García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Caenorhabditis Elegans ◽  
Protein Aggregation ◽  
Steroid Hormones ◽  
Sensory Neurons ◽  
Environmental Cues ◽  
Steroid Sulfatase ◽  
Loss Of Function ◽  
C Elegans ◽  
Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

scholarly journals Specific collagens maintain the cuticle permeability barrier in Caenorhabditis elegans

Genetics ◽  
2021 ◽  
Author(s):  
Anjali Sandhu ◽  
Divakar Badal ◽  
Riya Sheokand ◽  
Shalini Tyagi ◽  
Varsha Singh
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Barrier Function ◽  
Permeability Barrier ◽  
Nematode Caenorhabditis Elegans ◽  
Zinc Finger Transcription Factor ◽  
Outermost Layer ◽  
C Elegans ◽  
Receptor Mutant ◽  
Antioxidant Machinery

Abstract Collagen enriched cuticle forms the outermost layer of skin in nematode Caenorhabditis elegans. The nematode’s genome encodes 177 collagens, but little is known about their role in maintaining the structure or barrier function of the cuticle. In this study, we found six permeability determining (PD) collagens. Loss of any of these PD collagens- DPY-2, DPY-3, DPY-7, DPY-8, DPY-9, and DPY-10- led to enhanced susceptibility of nematodes to paraquat (PQ) and antihelminthic drugs levamisole and ivermectin. Upon exposure to paraquat, PD collagen mutants accumulated more PQ and incurred more damage and death despite the robust activation of antioxidant machinery. We find that BLMP-1, a zinc finger transcription factor, maintains the barrier function of the cuticle by regulating the expression of PD collagens. We show that the permeability barrier maintained by PD collagens acts in parallel to FOXO transcription factor DAF-16 to enhance survival of insulin-like receptor mutant, daf-2. In all, this study shows that PD collagens regulate cuticle permeability by maintaining the structure of C. elegans cuticle and thus provide protection against exogenous toxins.

scholarly journals The DM Domain Transcription Factor MAB-3 Regulates Male Hypersensitivity to Oxidative Stress in Caenorhabditis elegans

2010 ◽  
Vol 30 (14) ◽  
pp. 3453-3459 ◽  
Author(s):  
Hideki Inoue ◽  
Eisuke Nishida
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Sex Determination ◽  
Target Genes ◽  
Stress Sensitivity ◽  
Gata Factor ◽  
X Chromosomes ◽  
C Elegans ◽  
Dm Domain

ABSTRACT Sex differences occur in most species and involve a variety of biological characteristics. The nematode Caenorhabditis elegans consists of two sexes, self-fertile hermaphrodites (XX) and males (XO). Males differ from hermaphrodites in morphology, behavior, and life span. Here, we find that male C. elegans worms are much more sensitive than hermaphrodites to oxidative stress and show that the DM domain transcription factor MAB-3 plays a pivotal role in determining this male hypersensitivity. The hypersensitivity to oxidative stress does not depend on the dosage of X chromosomes but is determined by the somatic sex determination pathway. Our analyses show that the male hypersensitivity is controlled by MAB-3, one of the downstream effectors of the master terminal switch TRA-1 in the sex determination pathway. Moreover, we find that MAB-3 suppresses expression of several transcriptional target genes of the ELT-2 GATA factor, which is a global regulator of transcription in the C. elegans intestine, and show that RNA interference (RNAi) against elt-2 increases sensitivity to oxidative stress. These results strongly suggest that the DM domain protein MAB-3 regulates oxidative stress sensitivity by repressing transcription of ELT-2 target genes in the intestine.

scholarly journals bZIP transcription factor zip-2 mediates an early response to Pseudomonas aeruginosa infection in Caenorhabditis elegans

2010 ◽  
Vol 107 (5) ◽  
pp. 2153-2158 ◽  
Author(s):  
Kathleen A. Estes ◽  
Tiffany L. Dunbar ◽  
Jennifer R. Powell ◽  
Frederick M. Ausubel ◽  
Emily R. Troemel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Bacterial Pathogen ◽  
Early Response ◽  
Bzip Transcription Factor ◽  
Wild Type ◽  
Response Gene ◽  
C Elegans ◽  
Infection Response

Very little is known about how animals discriminate pathogens from innocuous microbes. To address this question, we examined infection-response gene induction in the nematode Caenorhabditis elegans. We focused on genes that are induced in C. elegans by infection with the bacterial pathogen Pseudomonas aeruginosa, but are not induced by an isogenic attenuated gacA mutant. Most of these genes are induced independently of known immunity pathways. We generated a GFP reporter for one of these genes, infection response gene 1 (irg-1), which is induced strongly by wild-type P. aeruginosa strain PA14, but not by other C. elegans pathogens or by other wild-type P. aeruginosa strains that are weakly pathogenic to C. elegans. To identify components of the pathway that induces irg-1 in response to infection, we performed an RNA interference screen of C. elegans transcription factors. This screen identified zip-2, a bZIP transcription factor that is required for inducing irg-1, as well as several other genes, and is important for defense against infection by P. aeruginosa. These data indicate that zip-2 is part of a specialized pathogen response pathway that is induced by virulent strains of P. aeruginosa and provides defense against this pathogen.

scholarly journals Manganese disturbs metal and protein homeostasis in Caenorhabditis elegans

Metallomics ◽  
2014 ◽  
Vol 6 (10) ◽  
pp. 1816-1823 ◽  
Author(s):  
Suzanne Angeli ◽  
Tracy Barhydt ◽  
Ross Jacobs ◽  
David W. Killilea ◽  
Gordon J. Lithgow ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Protein Homeostasis ◽  
C Elegans ◽  
Metal Composition

Mn feeding induces altered metal composition and degrades protein homeostasis inC. elegans.

Long-term sediment exposure to ZnO nanoparticles induces oxidative stress in Caenorhabditis elegans

2019 ◽  
Vol 6 (8) ◽  
pp. 2602-2614 ◽  
Author(s):  
Chi-Wei Huang ◽  
Shang-Wei Li ◽  
Vivian Hsiu-Chuan Liao
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Zno Nanoparticles ◽  
Gene Activation ◽  
Benthic Organism ◽  
Zno Nps ◽  
C Elegans ◽  
Sediment Exposure

Long-term sediment exposure to ZnO-NPs induces oxidative stress in benthic organism C. elegans which is mediated by the transcription factor DAF-16/FOXO triggering stress-responsive gene activation.

scholarly journals elt-1, an embryonically expressed Caenorhabditis elegans gene homologous to the GATA transcription factor family.

1991 ◽  
Vol 11 (9) ◽  
pp. 4651-4659 ◽  
Author(s):  
J Spieth ◽  
Y H Shim ◽  
K Lea ◽  
R Conrad ◽  
T Blumenthal
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Dna Binding ◽  
Single Copy ◽  
Amino Acid Sequences ◽  
Recognition Sequence ◽  
Sequence Element ◽  
C Elegans ◽  
Binding Domains ◽  
Degenerate Oligonucleotide

The short, asymmetrical DNA sequence to which the vertebrate GATA family of transcription factors binds is present in some Caenorhabditis elegans gene regulatory regions: it is required for activation of the vitellogenin genes and is also found just 5' of the TATA boxes of tra-2 and the msp genes. In vertebrates GATA-1 is specific to erythroid lineages, whereas GATA-2 and GATA-3 are present in multiple tissues. In an effort to identify the trans-acting factors that may recognize this sequence element in C. elegans, we used a degenerate oligonucleotide to clone a C. elegans homolog to this gene. We call this gene elt-1 (erythrocytelike transcription factor). It is single copy and specifies a 1.75-kb mRNA that is present predominantly, if not exclusively, in embryos. The region of elt-1 encoding two zinc fingers is remarkably similar to the DNA-binding domain of the vertebrate GATA-binding proteins. However, outside of the DNA-binding domains the amino acid sequences are quite divergent. Nevertheless, introns are located at identical or nearly identical positions in elt-1 and the mouse GATA-1 gene. In addition, elt-1 mRNA is trans-spliced to the 22-base untranslated leader, SL1. The DNA upstream of the elt-1 TATA box contains eight copies of the GATA recognition sequence within the first 300 bp, suggesting that elt-1 may be autogenously regulated. Our results suggest that the specialized role of GATA-1 in erythroid gene expression was derived after separation of the nematodes and the line that led to the vertebrates, since C. elegans lacks an erythroid lineage.

elt-1, an embryonically expressed Caenorhabditis elegans gene homologous to the GATA transcription factor family

1991 ◽  
Vol 11 (9) ◽  
pp. 4651-4659
Author(s):  
J Spieth ◽  
Y H Shim ◽  
K Lea ◽  
R Conrad ◽  
T Blumenthal
Keyword(s):  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Dna Binding ◽  
Single Copy ◽  
Amino Acid Sequences ◽  
Recognition Sequence ◽  
Sequence Element ◽  
C Elegans ◽  
Binding Domains ◽  
Degenerate Oligonucleotide

The short, asymmetrical DNA sequence to which the vertebrate GATA family of transcription factors binds is present in some Caenorhabditis elegans gene regulatory regions: it is required for activation of the vitellogenin genes and is also found just 5' of the TATA boxes of tra-2 and the msp genes. In vertebrates GATA-1 is specific to erythroid lineages, whereas GATA-2 and GATA-3 are present in multiple tissues. In an effort to identify the trans-acting factors that may recognize this sequence element in C. elegans, we used a degenerate oligonucleotide to clone a C. elegans homolog to this gene. We call this gene elt-1 (erythrocytelike transcription factor). It is single copy and specifies a 1.75-kb mRNA that is present predominantly, if not exclusively, in embryos. The region of elt-1 encoding two zinc fingers is remarkably similar to the DNA-binding domain of the vertebrate GATA-binding proteins. However, outside of the DNA-binding domains the amino acid sequences are quite divergent. Nevertheless, introns are located at identical or nearly identical positions in elt-1 and the mouse GATA-1 gene. In addition, elt-1 mRNA is trans-spliced to the 22-base untranslated leader, SL1. The DNA upstream of the elt-1 TATA box contains eight copies of the GATA recognition sequence within the first 300 bp, suggesting that elt-1 may be autogenously regulated. Our results suggest that the specialized role of GATA-1 in erythroid gene expression was derived after separation of the nematodes and the line that led to the vertebrates, since C. elegans lacks an erythroid lineage.

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