mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing

Borbolis, Fivos; Rallis, John; Kanatouris, George; Kokla, Nikolitsa; Karamalegkos, Antonis; Vasileiou, Christina; Vakaloglou, Katerina M.; Diallinas, George; Stravopodis, Dimitrios J.; Zervas, Christos G.; Syntichaki, Popi

doi:10.7554/elife.53757

Cited by 6 publications

(8 citation statements)

References 58 publications

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“…RNAi experiments in worms were performed on NGM plates seeded with E. coli HT115 (DE3) bacteria transformed with the indicated RNAi construct (primers listed in Supplementary Table S2) or the appropriate empty vector (plasmid L4440 or T444T purchased from Addgene, Watertown, MA, USA). All RNAi assays were performed at 20 • C, as previously described [48]. For human LonP1 small interfering RNA (siRNA) experiments, dicer-substrate RNA (DsiRNA) duplexes (5 -AAUCAGAGUGUGGCAUAGAAGCUAT-3 ) were purchased from Integrated DNA Technologies (IDT, Coralville, IA, USA).…”

Section: Rna Interferencementioning

confidence: 99%

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Taouktsi

Kyriakou

Smyrniotis

et al. 2022

Cells

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Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.

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Section: Rna Interferencementioning

confidence: 99%

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Taouktsi

Kyriakou

Smyrniotis

et al. 2022

Cells

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“…Although the biological function of this translocation to PBs is not yet understood, the involvement of decapping in translational control during aging seems to be essential, since C. elegans decapping mutants are significantly short-lived [129,130]. However, neuronal overexpression of DCAP-1 is sufficient to increase lifespan, through the function of the insulin/IGF-like signaling (IIS) pathway and its effector DAF-16/FOXO [132]. IIS is a central pathway that integrates developmental and stress signals and regulates development, stress response and longevity in various organisms [133].…”

Section: Biological Implications Of Decapping In Worms and Fliesmentioning

confidence: 99%

“…IIS is a central pathway that integrates developmental and stress signals and regulates development, stress response and longevity in various organisms [133]. Excess of DCAP-1 in neurons destabilizes the mRNA of insulin-like peptide INS-7, reducing its neurosecretion, and ultimately affecting the function of IIS and DAF-16 in distal tissues [132]. Since neuroendocrine regulation of lifespan is a common phenomenon across species [133][134][135], similar mechanisms are expected to apply in other organisms.…”

Section: Biological Implications Of Decapping In Worms and Fliesmentioning

confidence: 99%

“…Since neuroendocrine regulation of lifespan is a common phenomenon across species [133][134][135], similar mechanisms are expected to apply in other organisms. Indeed, neuron-specific overexpression of DCP1 in D. melanogaster extends lifespan of adult flies, while its knockdown has the opposite effect [132]. Neuronal decapping activity has also been implicated in the coordination of developmental events; DCP1 null mutations in flies result in lethality during pupation [136], and neuron-specific knockdown of D. melanogaster DCP1 gene impairs wing morphogenesis and expansion in a cell nonautonomous manner [132].…”

Section: Biological Implications Of Decapping In Worms and Fliesmentioning

confidence: 99%

“…Indeed, neuron‐specific overexpression of DCP1 in D. melanogaster extends lifespan of adult flies, while its knockdown has the opposite effect [132]. Neuronal decapping activity has also been implicated in the coordination of developmental events; DCP1 null mutations in flies result in lethality during pupation [136], and neuron‐specific knockdown of D. melanogaster DCP1 gene impairs wing morphogenesis and expansion in a cell nonautonomous manner [132]. Likewise, neuronal loss of dcap‐1/dcap‐2 in C. elegans disrupts early developmental decisions under elevated temperatures, through impaired execution of miRNA‐regulated developmental timing mechanisms [137].…”

Section: Biological Implications Of Decapping In Worms and Fliesmentioning

confidence: 99%

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Biological implications of decapping: beyond bulk mRNA decay

Borbolis

Syntichaki

2021

The FEBS Journal

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It is well established that mRNA steady-state levels do not directly correlate with transcription rate. This is attributed to the multiple posttranscriptional mechanisms, which control both mRNA turnover and translation within eukaryotic cells. One such mechanism is the removal of the 5' end cap structure of RNAs (decapping). This 5' cap plays a fundamental role in cellular functions related to mRNA processing, transport, translation, quality control, and decay, while its chemical modifications influence the fate of cytoplasmic mRNAs. Decapping is a highly controlled process, performed by multiple decapping enzymes, and regulated by complex cellular networks. In this review, we provide an updated synopsis of 5' end modifications and functions, and give an overview of mRNA decapping enzymes, presenting their enzymatic properties. Focusing on DCP2 decapping enzyme, a major component on the 5'-3' mRNA decay pathway, we describe cis-elements and transacting factors that affect its activity, substrate specificity, and cellular localization. Finally, we discuss current knowledge on the biological functions of mRNA decapping and decay factors, highlighting the major questions that remain to be addressed.

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The role of Kinesin-1 in neuronal dense core vesicle transport and lifespan regulation inC. elegans

Gavrilova,

Boström,

Korabel

et al. 2024

Preprint

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Fast axonal transport is crucial for neuronal function and is driven by kinesins and cytoplasmic dynein. We investigated the role of the kinesin-1 motor complex in dense core vesicle (DCV) transport in C. elegans, using mutants in kinesin light chains (klc-1 and klc-2) and the kinesin motor subunit (unc-116) expressing an ida-1::gfp transgene that labels DCVs in the ALA neuron. A reduced-function unc-116(rf) mutation greatly impaired DCV transport in both directions. A klc-2(rf) reduced-function mutation decreased DCV velocity in both directions and reduced the frequency of body bends during swimming. In contrast, the klc-1(-) null mutation had no effect on anterograde transport or swimming ability, but surprisingly it increased the speed of retrograde DCV transport. We also determined lifespan, finding that klc-1(-) or klc-2(rf) single mutants were wild-type whereas the unc-116(rf), ida-1::gfp and unc-116(rf); ida-1::gfp strains were short-lived. Strikingly, the ida-1::gfp transgenic synergistically interact with either klc mutant to extend lifespan compared to wild-type and parental strains. Our findings suggest that kinesin-1 not only influences anterograde and retrograde DCV transport but also plays a role in regulating lifespan.

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mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing

Cited by 6 publications

References 58 publications

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease

Biological implications of decapping: beyond bulk mRNA decay

The role of Kinesin-1 in neuronal dense core vesicle transport and lifespan regulation inC. elegans

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