The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans

Moll, Lorna; Roitenberg, Noa; Bejerano‐Sagie, Michal; Boocholez, Hana; Marques, Filipa Carvalhal; Volovik, Yuli; Elami, Tayir; Siddiqui, Atif Ahmed; Grushko, Danielle; Biram, Adi; Lampert, Bar; Achache, Hana; Ravid, Tommer; Tzur, Yonatan B; Cohen, Ehud

doi:10.7554/elife.38635

Cited by 22 publications

(25 citation statements)

References 54 publications

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“…A recent study implicated SUMOylation of the germline RNA binding protein CAR-1 (cytokinesis, apoptosis, RNA-associated), in the regulation of lifespan by insulin signalling. Under low insulin signalling conditions (in daf-2 mutants), CAR-1 is less likely to be SUMO-modified, and can effectively inhibit glp-1 expression in the germline, allowing for lifespan extension 28 . Our findings indicate that DAF-16 and SKN-1 mediate the effects of SUMO on ageing, in the soma.…”

Section: Discussionmentioning

confidence: 99%

“…SUMOylation has been mainly studied in the context of development in C. elegans , and has been implicated in embryonic, vulval and muscle development, and in DNA damage responses 16 – 27 . Recently, SUMOylation of a specific RNA binding protein (CAR-1) in the germline has been linked to organismal ageing 28 . Notably, the level of SUMO1 modified proteins has been shown to progressively increase during ageing in blood plasma and cortical lysates of mice 29 .…”

Section: Introductionmentioning

confidence: 99%

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SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

Princz

Pelisch

Tavernarakis

2020

Sci Rep

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The insulin/IGF signalling pathway impacts lifespan across distant taxa, by controlling the activity of nodal transcription factors. In the nematode Caenorhabditis elegans, the transcription regulators DAF-16/FOXO and SKN-1/Nrf function to promote longevity under conditions of low insulin/IGF signalling and stress. The activity and subcellular localization of both DAF-16 and SKN-1 is further modulated by specific posttranslational modifications, such as phosphorylation and ubiquitination. Here, we show that ageing elicits a marked increase of SUMO levels in C. elegans. In turn, SUMO fine-tunes DAF-16 and SKN-1 activity in specific C. elegans somatic tissues, to enhance stress resistance. SUMOylation of DAF-16 modulates mitochondrial homeostasis by interfering with mitochondrial dynamics and mitophagy. Our findings reveal that SUMO is an important determinant of lifespan, and provide novel insight, relevant to the complexity of the signalling mechanisms that influence gene expression to govern organismal survival in metazoans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

Princz

Pelisch

Tavernarakis

2020

Sci Rep

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“…Here, we have shown in C. elegans that CAR‐1, similarly to other P‐body components, assembles into SGs in response to heat shock. This result is interesting in the context of recent work demonstrating that CAR‐1 increases animal resistance to heat shock when constitutively expressed under its non‐SUMOylatable translation repressor form . Thus, this raises the possibility that the aggregation of CAR‐1 and repressed mRNA targets into SGs may participate to the cellular adaptation to heat shock.…”

Section: Discussionmentioning

confidence: 80%

Detecting and quantifying stress granules in tissues of multicellular organisms with the Obj.MPP analysis tool

Graeve

Debreuve

Rahmoun

et al. 2019

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Stress granules (SGs) are macromolecular assemblies induced by stress and composed of proteins and mRNAs stalled in translation initiation. SGs play an important role in the response to stress and in the modulation of signaling pathways. Furthermore, these structures are related to the pathological ribonucleoprotein (RNP) aggregates found in neurodegenerative disease contexts, highlighting the need to understand how they are formed and recycled in normal and pathological contexts. Although genetically tractable multicellular organisms have been key in identifying modifiers of RNP aggregate toxicity, in vivo analysis of SG properties and regulation has lagged behind, largely due to the difficulty of detecting SG from images of intact tissues.Here, we describe the object detector software Obj.MPP and show how it overcomes the limits of classical object analyzers to extract the properties of SGs from wide-field and confocal images of Caenorhabditis elegans and Drosophila tissues, respectively.We demonstrate that Obj.MPP enables the identification of genes modulating the assembly of endogenous and pathological SGs, and thus that it will be useful in the context of future genetic screens and in vivo studies. K E Y W O R D Sdetection algorithm, image analysis, marked point process, stress granules

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“…Indeed, both SKN-1 and DAF-16 were shown to regulate the mitophagy mediator dct-1 to regulate mitochondrial health [49]. This theme is also supported by the observation that the IIS and proteostasis-maintaining signaling that originate from the reproductive system are linked at the post-translational level [50] and by the recently reported integration of signals that originate from the reproductive system and from the IIS [51].…”

Section: Discussionmentioning

confidence: 91%

Temporal Requirements of SKN-1/NRF as a Regulator of Lifespan and Proteostasis inCaenorhabditis elegans

Grushko

Levine

Boocholez

et al. 2020

Preprint

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Lowering 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.

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The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans

Cited by 22 publications

References 54 publications

SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

SUMO promotes longevity and maintains mitochondrial homeostasis during ageing in Caenorhabditis elegans

Detecting and quantifying stress granules in tissues of multicellular organisms with the Obj.MPP analysis tool

Temporal Requirements of SKN-1/NRF as a Regulator of Lifespan and Proteostasis inCaenorhabditis elegans

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