GRSF1 suppresses cell senescence

Noh, Ji Heon; Kim, Kyoung Mi; Idda, Maria Laura; Martindale, Jennifer L.; Yang, Xiaoling; Abdelmohsen, Kotb; Gorospe, Myriam

doi:10.18632/aging.101516

Cited by 20 publications

(19 citation statements)

References 26 publications

(31 reference statements)

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“…We recently reported that the DNA damage and impaired cell proliferation seen in cells in which GRSF1 was depleted mirrored the phenotype of senescent cells ( 18 ), supporting the view that GRSF1 prevented premature senescence by preserving mitochondrial function. Accordingly, GRSF1-depleted cells were growth arrested, displayed senescence markers such as cyclin-dependent kinase inhibitors (p21 and p16) and a senescence-associated β-galactosidase activity ( 18 ). Importantly, GRSF1 depletion also led to the production of a pivotal senescence-associated factor, the pro-inflammatory cytokine interleukin (IL)6.…”

Section: Introductionmentioning

confidence: 68%

“…Accordingly, loss of GRSF1 impaired mitochondrial oxidative phosphorylation and elevated ROS, triggering a DNA damage response that in turn activated mTOR and NF-κB, and increasing the production and secretion of pro-inflammatory factors, notably IL6 (Figure 7D ). Given this evidence, we propose that the loss of GRSF1 observed in senescent cells contributes to the senescence-associated rise in oxidative stress, DNA damage, growth arrest, and IL6 production ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of RNA-binding protein GRSF1 activates mTOR to elicit a proinflammatory transcriptional program

Noh

Kim

Pandey

et al. 2019

Nucleic Acids Research

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The RNA-binding protein GRSF1 (G-rich RNA sequence-binding factor 1) critically maintains mitochondrial homeostasis. Accordingly, loss of GRSF1 impaired mitochondrial respiration and increased the levels of reactive oxygen species (ROS), triggering DNA damage, growth suppression, and a senescent phenotype characterized by elevated production and secretion of interleukin (IL)6. Here, we characterize the pathways that govern IL6 production in response to mitochondrial dysfunction in GRSF1-depleted cells. We report that loss of GRSF1 broadly altered protein expression programs, impairing the function of respiratory complexes I and IV. The rise in oxidative stress led to increased DNA damage and activation of mTOR, which in turn activated NF-κB to induce IL6 gene transcription and orchestrate a pro-inflammatory program. Collectively, our results indicate that GRSF1 helps preserve mitochondrial homeostasis, in turn preventing oxidative DNA damage and the activation of mTOR and NF-κB, and suppressing a transcriptional pro-inflammatory program leading to increased IL6 production.

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“…In particular, ERK1/2 regulates senescence-associated proteins including RSKs, Sprouty, and MYC (Campaner et al 2010;Macia et al 2014;Munoz-Espin and Serrano 2014;Sun et al 2018) and p38 regulates ATF6, ZNHIT1, HBP1, p53, MK2, and MK5 (Zhang et al 2006;Sun et al 2007;Debacq-Chainiaux et al 2010;Druelle et al 2016;Macedo et al 2018). Besides regulating transcription of senescenceassociated genes, MAPKs and their effectors (e.g., MNK1, MK2, RSKs) can also control gene expression programs post-transcriptionally by phosphorylating and thereby modulating the activity of RNA-binding proteins (RBPs) implicated in senescence, such as HuR, AUF1, PTBP1, TTP, GRSF1, and hnRNPA1 (Wang et al 2005;Wang et al 2016;Ziaei et al 2012;Alspach et al 2014;Wiley and Campisi 2016;Georgilis et al 2018;Noh et al 2018;Noh et al 2019). Phosphorylation by MAPKs often alters the ability of RBPs to bind target mRNAs, as shown for HuR, TTP, and AUF1, and modulates the fate of these mRNAs (Grammatikakis et al 2017;Soni et al 2019).…”

Section: Mapk Network In Cellular Senescencementioning

confidence: 99%

Regulation of senescence traits by MAPKs

2020

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A phenotype of indefinite growth arrest acquired in response to sublethal damage, cellular senescence affects normal aging and age-related disease. Mitogen-activated protein kinases (MAPKs) are capable of sensing changes in cellular conditions, and in turn elicit adaptive responses including cell senescence. MAPKs modulate the levels and function of many proteins, including proinflammatory factors and factors in the p21/p53 and p16/RB pathways, the main senescence-regulatory axes. Through these actions, MAPKs implement key traits of senescence-growth arrest, cell survival, and the senescence-associated secretory phenotype (SASP). In this review, we summarize and discuss our current knowledge of the impact of MAPKs in senescence. In addition, given that eliminating or suppressing senescent cells can improve health span, we discuss the function and possible exploitation of MAPKs in the elimination (senolysis) or suppression (senostasis) of senescent cells.

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“…When these granules aberrantly accumulate, the integrity of cristae is compromised to accommodate them 71 . GRSF1, a nuclear encoded RNA-binding protein that regulates RNA processing in mitochondrial RNA granules 62 and is critical for maintaining mitochondrial function 63,75 , was significantly decreased in our mitochondrial proteomic dataset in HD. GRSF1 has also been implicated in cellular senescence with levels declining in senescent cells and lowered GRSF1 levels causing mitochondrial stress 63 .…”

Section: Discussionmentioning

confidence: 85%

CryoET Reveals Organelle Phenotypes in Huntington Disease Patient iPSC-Derived and Mouse Primary Neurons

Smith-Geater

Galaz-Montoya

et al. 2022

Preprint

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Huntington's Disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. Patient-derived induced pluripotent stem cells (iPSCs) can help understand disease; however, defining pathological biomarkers is challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered mitochondria with enlarged granules and distorted cristae, and thin sheet aggregates in double membrane-bound organelles. We used artificial intelligence to quantify mitochondrial granules, and proteomics to show differential protein content in HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC-neurons and reduced phenotypes in BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

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“…This protein is essential for mitochondrial function and required for mitochondrial RNA processing 62 . Indeed, loss of GRSF1 causes mitochondrial stress and can induce senescence phenotypes 63 . Panther pathway analysis identified cytoskeletal regulation by Rho GTPase and pyrimidine metabolism as two other of the three most overrepresented pathways by the DEPs (Fig.…”

Section: Mitochondrial Proteomics Of Human Ipsc-derived Neurons Ident...mentioning

confidence: 99%

CryoET Reveals Organelle Phenotypes in Huntington Disease Patient iPSC-Derived and Mouse Primary Neurons

Chiu

Galaz-Montoya

et al. 2022

Preprint

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Huntington’s Disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. Patient-derived induced pluripotent stem cells (iPSCs) can help understand disease; however, defining pathological biomarkers is challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered mitochondria with enlarged granules and distorted cristae, and thin sheet aggregates in double membrane-bound organelles. We used artificial intelligence to quantify mitochondrial granules, and proteomics showed differential protein content in HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC-neurons and reduced phenotypes in BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

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GRSF1 suppresses cell senescence

Cited by 20 publications

References 26 publications

Loss of RNA-binding protein GRSF1 activates mTOR to elicit a proinflammatory transcriptional program

Regulation of senescence traits by MAPKs

CryoET Reveals Organelle Phenotypes in Huntington Disease Patient iPSC-Derived and Mouse Primary Neurons

CryoET Reveals Organelle Phenotypes in Huntington Disease Patient iPSC-Derived and Mouse Primary Neurons

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