Transdifferentiation mediated tumor suppression by the endoplasmic reticulum stress sensor IRE-1 in C. elegans

Levi-Ferber, Mor; Gian, Hai; Dudkevich, Reut; Henis-Korenblit, Sivan

doi:10.7554/elife.08005

Cited by 10 publications

(22 citation statements)

References 42 publications

(54 reference statements)

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“…3 A). ire-1(ok799) is a null mutation ( Roux et al, 2016 ), xbp-1(tm2457) is a deletion at the 3′ end of the gene ( Levi-Ferber et al, 2015 ), and xbp-1(zc12) a stop codon at the 5′ end of the gene ( Calfon et al, 2002 ). Because mutants carrying these alleles are extremely sensitive to TM ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Auxin confers protection against ER stress in Caenorhabditis elegans

2021

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Auxins are plant growth regulators that influence most aspects of plant development through complex mechanisms. The development of an auxin-inducible degradation (AID) system has enabled rapid, conditional protein depletion in yeast and cultured cells. More recently, the system was successfully adapted to Caenorhabditiselegans to achieve auxin-dependent degradation of targets in all tissues and developmental stages. Whether auxin treatment alone has an impact on nematode physiology is an open question. Here we show that indole-3-acetic acid (IAA), the auxin most commonly used to trigger AID in worms, functions through the conserved IRE-1/XBP-1 branch of the Unfolded Protein Response (UPR) to promote resistance to endoplasmic reticulum (ER) stress. Because the UPR not only plays a central role in restoring ER homeostasis, but also promotes lipid biosynthesis and regulates lifespan, we suggest that extreme caution should be exercised when using the AID system to study these and related processes.

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Section: Resultsmentioning

confidence: 99%

Auxin confers protection against ER stress in Caenorhabditis elegans

2021

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“…The tumorous germline of gld-1(- ) animals is prone to undergo ectopic differentiation into somatic cells, which are cleared away from the gonad by programmed cell death followed by corpse absorbance by the surrounding tissues ( Ciosk et al, 2006 ; Levi-Ferber et al, 2015 ). These abnormal, ectopically differentiated cells can be identified based on the expression of somatic markers and based on their relatively enlarged and irregularly shaped nuclei, which are distinct from the typical nuclei of the germline cells.…”

Section: Resultsmentioning

confidence: 99%

“…The ER-UPR consists of signaling pathways that help to restore ER homeostasis by reducing the load on the ER and degrading misfolded proteins ( Walter and Ron, 2011 ). Previously we have shown that activation of the conserved UPR sensor inositol requiring enzyme-1 (IRE-1) enhances ectopic differentiation of the tumorous germline in gld-1 -deficient C. elegans , which limits the progression of the lethal germline tumor ( Levi-Ferber et al, 2015 ). Although the major signaling mode of action of IRE-1 is to generate an active form of the ER stress-related transcription factor xbp-1 (X-box binding protein-1), ER stress-induced GED requires the ire-1 gene, but not its downstream target xbp-1.…”

Section: Introductionmentioning

confidence: 99%

“…Although the major signaling mode of action of IRE-1 is to generate an active form of the ER stress-related transcription factor xbp-1 (X-box binding protein-1), ER stress-induced GED requires the ire-1 gene, but not its downstream target xbp-1. The nature of this ire-1- dependent xbp-1 -independent signal remains a mystery ( Levi-Ferber et al, 2015 ). xbp-1 -independent outputs of ire-1 include activation of signaling cascades by virtue of IRE-1 oligomerization ( Urano et al, 2000 ; Yoneda et al, 2001 ), and degradation of ER-localized mRNAs by virtue of IRE-1 ribonuclease activity—a process called regulated Ire1-dependent decay (RIDD) ( Hollien and Weissman, 2006 ; Hollien et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal regulated ire-1-dependent mRNA decay controls germline differentiation in Caenorhabditis elegans

Levi-Ferber

Shalash

Le-Thomas³

et al. 2021

eLife

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Understanding the molecular events that regulate cell pluripotency versus acquisition of differentiated somatic cell fate is fundamentally important. Studies in Caenorhabditis elegans demonstrate that knockout of the germline-specific translation repressor gld-1 causes germ cells within tumorous gonads to form germline-derived teratoma. Previously we demonstrated that endoplasmic reticulum (ER) stress enhances this phenotype to suppress germline tumor progression(Levi-Ferber et al., 2015). Here, we identify a neuronal circuit that non-autonomously suppresses germline differentiation and show that it communicates with the gonad via the neurotransmitter serotonin to limit somatic differentiation of the tumorous germline. ER stress controls this circuit through regulated inositol requiring enzyme-1 (IRE-1)-dependent mRNA decay of transcripts encoding the neuropeptide FLP-6. Depletion of FLP-6 disrupts the circuit’s integrity and hence its ability to prevent somatic-fate acquisition by germline tumor cells. Our findings reveal mechanistically how ER stress enhances ectopic germline differentiation and demonstrate that regulated Ire1-dependent decay can affect animal physiology by controlling a specific neuronal circuit.

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“…IRE1 also cleaves and initiates the degradation of other mRNAs associated with the ER membrane. This pathway, termed regulated IRE1-dependent decay (RIDD), is independent of XBP1 and conserved across many species (Kimmig et al, 2012; Coelho et al, 2013; Levi-Ferber et al, 2015). In mammalian cells, IRE1 typically degrades only a few mRNAs that contain specific translationally stalled stem-loop structures (Moore and Hollien, 2015), making this an unlikely mechanism to reduce the protein folding load on the ER.…”

Section: Introductionmentioning

confidence: 99%

Degradation of Blos1 mRNA by IRE1 repositions lysosomes and protects cells from stress

Bae

Moore

Mella

et al. 2019

Journal of Cell Biology

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Cells respond to stress in the ER by initiating the widely conserved unfolded protein response. Activation of the ER transmembrane nuclease IRE1 leads to the degradation of specific mRNAs, but how this pathway affects the ability of cells to recover from stress is not known. Here, we show that degradation of the mRNA encoding biogenesis of lysosome-related organelles 1 subunit 1 (Blos1) leads to the repositioning of late endosomes (LEs)/lysosomes to the microtubule-organizing center in response to stress in mouse cells. Overriding Blos1 degradation led to ER stress sensitivity and the accumulation of ubiquitinated protein aggregates, whose efficient degradation required their independent trafficking to the cell center and the LE-associated endosomal sorting complexes required for transport. We propose that Blos1 regulation by IRE1 promotes LE-mediated microautophagy of protein aggregates and protects cells from their cytotoxic effects.

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Transdifferentiation mediated tumor suppression by the endoplasmic reticulum stress sensor IRE-1 in C. elegans

Cited by 10 publications

References 42 publications

Auxin confers protection against ER stress in Caenorhabditis elegans

Auxin confers protection against ER stress in Caenorhabditis elegans

Neuronal regulated ire-1-dependent mRNA decay controls germline differentiation in Caenorhabditis elegans

Degradation of Blos1 mRNA by IRE1 repositions lysosomes and protects cells from stress

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