MAPK- and glycogen synthase kinase 3–mediated phosphorylation regulates the DEAD-box protein modulator Gle1 for control of stress granule dynamics

Aditi,; Mason, Aaron C.; Sharma, Manisha; Dawson, T. Renee; Wente, Susan R.

doi:10.1074/jbc.ra118.005749

Cited by 22 publications

(29 citation statements)

References 86 publications

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“…In addition, mutations affecting the DDX3X ATPase are involved in some types of medulloblastoma where cells demonstrate constitutive SG-like aggregates [110,126]. Interestingly, loss-of-function mutations in the DBP regulator Gle1 result in a fatal degenerative motor neuron disease called lethal congenital contracture syndrome (LCCS), which may result from aberrant ribostasis [127,128]. Moreover, one mechanism of toxicity of repeat-expansion RNAs appears to be the formation of RNA aggregates through RNA-RNA interactions [25], which can sequester RBPs, thereby altering RNA processing in pathogenic manners [129][130][131][132].…”

Section: Dysregulation Of Rna Condensation and Diseasementioning

confidence: 99%

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Tauber

Parker

2020

Trends in Biochemical Sciences

169

132

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Ribonucleoprotein (RNP) granules are RNA-protein assemblies that are involved in multiple aspects of RNA metabolism and are linked to memory, development, and disease. Some RNP granules form, in part, through the formation of intermolecular RNA-RNA interactions. In vitro, such trans RNA condensation occurs readily, suggesting that cells require mechanisms to modulate RNA-based condensation. We assess the mechanisms of RNA condensation and how cells modulate this phenomenon. We propose that cells control RNA condensation through ATP-dependent processes, static RNA buffering, and dynamic post-translational mechanisms. Moreover, perturbations in these mechanisms can be involved in disease. This reveals multiple cellular mechanisms of kinetic and thermodynamic control that maintain the proper distribution of RNA molecules between dispersed and condensed forms. Ribonucleoprotein Granules Are Built via a Summation of Multivalent InteractionsEukaryotic cells contain a variety of ribonucleoprotein (RNP) granules (see Glossary). RNP granules are large non-membrane-bound assemblies of RNA and protein and are present in the nucleus and the cytosol. Examples of RNP granules include the nucleolus (the site of rRNA biogenesis), stress granules (SGs; which form from untranslating RNAs [1]), and neuronal granules (that are important for the transport and translation of synaptic mRNAs and synaptic plasticity [2]).RNP granules are members of a growing class of biological assemblies referred to as biomolecular condensates (reviewed in [3]). Biomolecular condensates are non-membranous assemblies that form through multivalent interactions between their components. Condensates differ from traditional assemblies in that the diverse and multivalent nature of the interactions allows condensates to be variable in their assembly and size and lack any unique stoichiometry or stereospecificity.RNP granules generally require a specific population of RNA for their formation and can be enriched for many RNAs. As examples, SGs and P-bodies (PBs) require a cytoplasmic population of untranslating RNAs, the nucleolus requires rRNA transcripts to maintain its organization [4], and nuclear paraspeckles require the NEAT1 long noncoding (lnc)RNA [5]. RNP granules also compartmentalize specific RNA-binding proteins (RBPs). For instance, distinct RBPs accumulate in SGs and PBs, although they can also share some components [6][7][8][9][10].RNP granules form from a summation of both protein-protein and RNA-RNA interactions between RNPs (Figure 1). Protein-protein interactions that promote RNP granule formation occur between RBPs bound to the RNA and can involve well-folded domains of RBPs [11]. For example, the G3BP1 protein can bind to mRNAs, and then through dimerization can increase the formation of SGs [12]. Many RNP granule proteins also contain intrinsically disordered Highlights Intermolecular RNA-RNA interactions contribute to the formation, content, and biophysical properties of many RNP granules. Cells utilize both genetically programmed and prom...

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Section: Dysregulation Of Rna Condensation and Diseasementioning

confidence: 99%

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Tauber

Parker

2020

Trends in Biochemical Sciences

169

132

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“…The Nterminal Gle1 region also contains a Nup155 binding domain, a predicted IDR and a recently reported stress-induced phosphorylation cluster ( Fig. 1A) (16,24). To investigate the mechanism of human Gle1 self-association, we employed a set of biochemical approaches.…”

Section: Gle1 Contains Two Distinct Regions That Govern Oligomerizationmentioning

confidence: 99%

“…Gle1B facilitates the terminal step of mRNA export through the NPC by activating DDX19B in an inositol hexakisphosphate (IP 6 )–dependent manner ( 4 , 9 , 10 , 13 ). In the cytoplasm, Gle1A is required for proper stress granule (SG) formation and translation initiation during cellular stress through IP 6 -independent modulation of DDX3 ( 3 , 5 , 6 , 16 ). In S. cerevisiae , IP 6 -dependent Gle1 regulation of Dbp5, the ortholog of DDX19B, also plays a role during translation termination ( 6 ).…”

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confidence: 99%

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Functions of Gle1 are governed by two distinct modes of self-association

Mason

Wente

2020

Journal of Biological Chemistry

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Gle1 is a conserved, essential regulator of DEAD-box RNA helicases, with critical roles defined in mRNA export, translation initiation, translation termination, and stress granule formation. Mechanisms that specify which, where and when DDXs are targeted by Gle1 are critical to understand. In addition to roles for stress-induced phosphorylation and inositol hexakisphosphate (IP6) binding in specifying Gle1 function, Gle1 oligomerizes via its N-terminal domain in a phosphorylation-dependent manner. However, a thorough analysis of the role for Gle1 self-association is lacking. Here, we find that Gle1 self-association is driven by two distinct regions: a coiled-coil domain and a novel ten amino acid aggregation prone region, both of which are necessary for proper Gle1 oligomerization. By exogenous expression in HeLa cells, we tested the function of a series of mutations that impact the oligomerization domains of the Gle1A and Gle1B isoforms. Gle1 oligomerization is necessary for many, but not all aspects of Gle1A and Gle1B function, and the requirements for each interaction domain differ. Whereas the coiled-coil domain and aggregation prone region additively contribute to competent mRNA export and stress granule formation, both self-association domains are independently required for regulation of translation under cellular stress. In contrast, Gle1 self-association is dispensable for phosphorylation and non-stressed translation initiation. Collectively, we reveal self-association functions as an additional mode of Gle1 regulation to ensure proper mRNA export and translation. This work also provides further insight into the mechanisms underlying human gle1 disease mutants found in prenatally lethal forms of arthrogryposis.

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“…For instance, G3BP1/2 is indispensable for SG formation in response to oxidative stress, while it is not upon osmotic stress [5,8]. Moreover, post-translational modifications of various proteins within SGs, including phosphorylation and arginine methylation, have been reported to contribute to the complexity of SG dynamics [9][10][11][12][13][14]. P-bodies are other RNP granules known to share many components with SGs, suggesting biochemical crosstalk between the two unique granule structures [15].…”

Section: Introductionmentioning

confidence: 99%

Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

Park

Choi

Cho

et al. 2020

IJMS

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Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.

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MAPK- and glycogen synthase kinase 3–mediated phosphorylation regulates the DEAD-box protein modulator Gle1 for control of stress granule dynamics

Cited by 22 publications

References 86 publications

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Functions of Gle1 are governed by two distinct modes of self-association

Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin

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