Active regulator of SIRT1 is required for ribosome biogenesis and function

Knight, John R. P.; Willis, Anne E.; Milner, Jo

doi:10.1093/nar/gkt129

Cited by 23 publications

(19 citation statements)

References 50 publications

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“…SIRT1 is a deacetylase that is transcribed in response to caloric restriction . It regulates epigenetic gene silencing, inhibits the transcription of rRNA and subsequently reduces ribosome biogenesis . This occurs upon alterations of the NAD+/NADH ratio activating the energy‐dependent nucleolar silencing complex (eNoSC) containing Nucleomethylin (NML), SIRT1, and SUV39H1 to drive epigenetic changes on the rDNA locus that result in the repression of rRNA transcription .…”

Section: Sirt1 and Ribosome Biogenesismentioning

confidence: 99%

The role of the ribosome in the regulation of longevity and lifespan extension

MacInnes¹

2016

WIREs RNA

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The most energy-consuming process that a cell must undertake to stay viable is the continuous biogenesis of ribosomes for the translation of RNA into protein. Given the inextricable links between energy consumption and cellular lifespan, it is not surprising that mutations and environmental cues that reduce ribosome biogenesis result in an extension of eukaryotic lifespan. This review goes into detail describing recent discoveries of different and often unexpected elements that play a role in the regulation of longevity by virtue of their ribosome biogenesis functions. These roles include controlling the transcription and processing of ribosomal RNA (rRNA), the translation of ribosomal protein (RP) genes, and the number of ribosomes overall. Together these findings suggest that a fundamental mechanism across eukaryotic species for extending lifespan is to slow down or halt the expenditure of cellular energy that is normally absorbed by the manufacturing and assembly of new ribosomes.

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Section: Sirt1 and Ribosome Biogenesismentioning

confidence: 99%

The role of the ribosome in the regulation of longevity and lifespan extension

MacInnes¹

2016

WIREs RNA

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“…Analyses were carried out as previously described (Knight et al 2013). Total RNA was isolated using TRIzol (Invitrogen) as per the manufacturer's instructions.…”

Section: Pre-rrna Northern Blottingmentioning

confidence: 99%

Cooling-induced SUMOylation of EXOSC10 down-regulates ribosome biogenesis

Knight

Bastide

Peretti

et al. 2016

RNA

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The RNA exosome is essential for 3 ′ processing of functional RNA species and degradation of aberrant RNAs in eukaryotic cells. Recent reports have defined the substrates of the exosome catalytic domains and solved the multimeric structure of the exosome complex. However, regulation of exosome activity remains poorly characterized, especially in response to physiological stress. Following the observation that cooling of mammalian cells results in a reduction in 40S:60S ribosomal subunit ratio, we uncover regulation of the nuclear exosome as a result of reduced temperature. Using human cells and an in vivo model system allowing whole-body cooling, we observe reduced EXOSC10 (hRrp6, Pm/Scl-100) expression in the cold. In parallel, both models of cooling increase global SUMOylation, leading to the identification of specific conjugation of SUMO1 to EXOSC10, a process that is increased by cooling. Furthermore, we define the major SUMOylation sites in EXOSC10 by mutagenesis and show that overexpression of SUMO1 alone is sufficient to suppress EXOSC10 abundance. Reducing EXOSC10 expression by RNAi in human cells correlates with the 3 ′ preribosomal RNA processing defects seen in the cold as well as reducing the 40S:60S ratio, a previously uncharacterized consequence of EXOSC10 suppression. Together, this work illustrates that EXOSC10 can be modified by SUMOylation and identifies a physiological stress where this regulation is prevalent both in vitro and in vivo.

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“…Additional study showed that SIRT1 activation by the endogenous active regulator of SIRT1 also attenuated eIF2α phosphorylation and regulated ribosome biogenesis. 27 These data suggested that coordination of deacetylation and dephosphorylation of eIF2α may also be critical for ISR signaling and cytoprotection.…”

mentioning

confidence: 92%

Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function

Lee

George

et al. 2017

Cell Death Differ

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Phosphorylation of the eukaryotic translation initiation factor, eIF2α, by stress-activated protein kinases and dephosphorylation by the growth arrest and DNA damage-inducible protein (GADD34)-containing phosphatase is a central node in the integrated stress response. Mass spectrometry demonstrated GADD34 acetylation at multiple lysines. Substituting K and K with alanines or glutamines did not impair GADD34's ability to recruit protein phosphatase 1α (PP1α) or eIF2α, suggesting that GADD34 acetylation did not modulate eIF2α phosphatase activity. Arsenite (Ars)-induced oxidative stress increased cellular GADD34 levels and enhanced Sirtuin 1 (SIRT1) recruitment to assemble a cytoplasmic complex containing GADD34, PP1α, eIF2α and SIRT1. Induction of GADD34 in WT MEFs paralleled the dephosphorylation of eIF2α (phosphoserine-51) and SIRT1 (phosphoserine-47). By comparison, eIF2α and SIRT1 were persistently phosphorylated in Ars-treated GADD34-/- MEFs. Expressing WT GADD34, but not a mutant unable to bind PP1α in GADD34-/- MEFs restored both eIF2α and SIRT1 dephosphorylation. SIRT1 dephosphorylation increased its deacetylase activity, measured in vitro and in cells. Loss of function of GADD34 or SIRT1 enhanced cellular p-eIF2α levels and attenuated cell death following Ars exposure. These results highlighted a novel role for the GADD34/PP1α complex in coordinating the dephosphorylation and reactivation of eIF2α and SIRT1 to determine cell fate following oxidative stress.

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Active regulator of SIRT1 is required for ribosome biogenesis and function

Cited by 23 publications

References 50 publications

The role of the ribosome in the regulation of longevity and lifespan extension

The role of the ribosome in the regulation of longevity and lifespan extension

Cooling-induced SUMOylation of EXOSC10 down-regulates ribosome biogenesis

Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function

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