Hsp90‐mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling

Mediani, Laura; Antoniani, Francesco; Galli, Veronica; Vinet, Jonathan; Carrà, Arianna Dorotea; Bigi, Ilaria; Tripathy, Vadreenath; Tiago, Tatiana; Cimino, Marco; Leo, Giuseppina; Amen, Triana; Kaganovich, Daniel; Cereda, Cristina; Pansarasa, Orietta; Mandrioli, Jessica; Tripathi, Priyanka; Troost, Dirk; Aronica, Eleonora; Büchner, Johannes; Goswami, Anand; Sterneckert, Jared; Alberti, Simon; Carra, Serena

doi:10.15252/embr.202051740

Cited by 43 publications

(47 citation statements)

References 97 publications

(171 reference statements)

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“…Also other inhibitory cues such as the RRAG GTPases (Ras related GTP binding proteins) and AMPK (AMP-activated protein kinase) suppress mTORC1 at lysosomes [reviewed in detail by Oakhill et al (2010); Kim and Guan (2019); Gonzalez et al (2020); Liu and Sabatini (2020); Fernandes and Demetriades (2021)]. A growing body of evidence shows that stress granules (SGs) constitute a nonmembranous compartment at which mTORC1 is inhibited under stress through several mechanisms (Takahara and Maeda, 2012;Thedieck et al, 2013;Wippich et al, 2013;Ramiscal et al, 2015;Lastres-Becker et al, 2016;Pla-Martin et al, 2020;Mediani et al, 2021). Whereas the molecular machinery mediating the recruitment and regulation of mTORC1 at lysosomes (Rabanal-Ruiz and Korolchuk, 2018;Condon and Sabatini, 2019;Kim and Guan, 2019) or SGs (Takahara and Maeda, 2012;Thedieck et al, 2013;Wippich et al, 2013;Mediani et al, 2021) has been investigated in much detail, recent studies shed light on the mechanisms tethering the TSC complex to lysosomes (Fitzian et al, 2021;Prentzell et al, 2021) and to SGs (Kosmas et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…A growing body of evidence shows that stress granules (SGs) constitute a nonmembranous compartment at which mTORC1 is inhibited under stress through several mechanisms (Takahara and Maeda, 2012;Thedieck et al, 2013;Wippich et al, 2013;Ramiscal et al, 2015;Lastres-Becker et al, 2016;Pla-Martin et al, 2020;Mediani et al, 2021). Whereas the molecular machinery mediating the recruitment and regulation of mTORC1 at lysosomes (Rabanal-Ruiz and Korolchuk, 2018;Condon and Sabatini, 2019;Kim and Guan, 2019) or SGs (Takahara and Maeda, 2012;Thedieck et al, 2013;Wippich et al, 2013;Mediani et al, 2021) has been investigated in much detail, recent studies shed light on the mechanisms tethering the TSC complex to lysosomes (Fitzian et al, 2021;Prentzell et al, 2021) and to SGs (Kosmas et al, 2021). In this mini-review we summarize the latest findings focusing on the interplay of the TSC complex with SGs and lysosomes.…”

Section: Introductionmentioning

confidence: 99%

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The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

Rehbein

Prentzell

Sandoval

et al. 2021

Front. Cell Dev. Biol.

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The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes via phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

Rehbein

Prentzell

Sandoval

et al. 2021

Front. Cell Dev. Biol.

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“…In contrast to the mechanisms governing SG formation, the process of SG clearance remains relatively obscure, with a handful of recent studies beginning to investigate this question (Wheeler et al, 2016;Amen and Kaganovich, 2020a;Marmor-Kollet et al, 2020;Hofmann et al, 2021;Mediani et al, 2021). There are a number of reasons for thinking that SG clearance is a key aspect of SG biology.…”

Section: Discussionmentioning

confidence: 99%

“…Further investigating the dynamics of stilbene-derived SGs, we discovered that SGs formed by resveratrol and piceatannol require at least one isoform of G3BP1 and have unusually rapid clearance kinetics. Resveratrol is known to bind to G3BP1, reducing its valency by displacing its binding partner -USP10 (Buchan et al, 2013;Wheeler et al, 2016;Kaganovich, 2017;Mediani et al, 2021). It is therefore interesting that it produces highly unstable SGs, that in many other aspects resemble SGs formed by conventional stresses such as heat, arsenite, and starvation.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol and related stilbene derivatives induce stress granules with distinct clearance kinetics

Amen

Guihur

Zelent

et al. 2021

MBoC

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Stress Granules are ribonucleoprotein functional condensates that form during stress conditions in all eukaryotic cells. Although their stress-survival function is far from clear, Stress Granules have been implicated in the regulation of many vital cellular pathways. Consequently, SG dysfunction is thought to be a mechanistic point of origin for many neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS). Additionally, SGs are thought to play a role in pathogenic pathways as diverse as viral infection and chemotherapy resistance. There is a growing consensus around the hypothesis that understanding the mechanistic regulation of SG physical properties is essential to understanding their function. Although the internal dynamics and condensation mechanisms of SGs have been broadly investigated, there have been fewer investigations into the timing of SG formation and clearance in live cells. Since the lifetime of SG persistence can be a key factor in their function and tendency towards pathological dysregulation, SG clearance mechanisms deserve particular attention. Here we show that resveratrol and its analogues, piceatannol, pterostilbene, and 3,4,5,4′ tetramethoxystilbene induce G3BP-dependent SG formation with atypically rapid clearance kinetics. Resveratrol binds to G3BP, thereby reducing its protein-protein association valency. We suggest that altering G3BP valency is a pathway for the formation of uniquely transient SGs.

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“…In other instances, the connection between SGs and stress resistance is less clear. A number of additional functions have been reported for SGs, including mRNA quality control, spatiotemporal control of gene expression, regulation of nucleocytoplasmic transport, prevention of pathological protein aggregation, regulation of cell growth and kinase signaling, and alleviation of reactive oxygen species (ROS) damage ( Kedersha and Anderson, 2007 ; Kedersha et al., 2005 , 2013 ; Khong et al., 2017 ; Mann et al., 2019 ; McGurk et al., 2018 ; Panas et al., 2016 ; Takahashi et al., 2013 ; Zhang et al., 2018 ; Mediani et al., 2021 ; Amen and Kaganovich, 2020b ). In the latter case, SGs are shown to be activated by oxidative stress ( Kato et al., 2019 ) and to promote survival by activating the antioxidant activity of USP10, thereby reducing ROS production ( Takahashi et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability

Amen

Kaganovich

2021

Cell Reports

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Summary The formation of stress granules (SGs) is an essential aspect of the cellular response to many kinds of stress, but its adaptive role is far from clear. SG dysfunction is implicated in aging-onset neurodegenerative diseases, prompting interest in their physiological function. Here, we report that during starvation stress, SGs interact with mitochondria and regulate metabolic remodeling. We show that SG formation leads to a downregulation of fatty acid β-oxidation (FAO) through the modulation of mitochondrial voltage-dependent anion channels (VDACs), which import fatty acids (FAs) into mitochondria. The subsequent decrease in FAO during long-term starvation reduces oxidative damage and rations FAs for longer use. Failure to form SGs, whether caused by the genetic deletion of SG components or an amyotrophic lateral sclerosis (ALS)-associated mutation, translates into an inability to downregulate FAO. Because metabolic dysfunction is a common pathological element of neurodegenerative diseases, including ALS, our findings provide a direction for studying the clinical relevance of SGs.

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Hsp90‐mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling

Cited by 43 publications

References 97 publications

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

Resveratrol and related stilbene derivatives induce stress granules with distinct clearance kinetics

Stress granules inhibit fatty acid oxidation by modulating mitochondrial permeability

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