Acetylation of intrinsically disordered regions regulates phase separation

Saito, Makoto; Heß, Daniel; Eglinger, Jan; Fritsch, Anatol; Kreysing, Moritz; Weinert, Brian T.; Choudhary, Chunaram; Matthias, Patrick

doi:10.1038/s41589-018-0180-7

Cited by 217 publications

(206 citation statements)

References 57 publications

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“…Molecular interactions between positively charged amino acids with nucleic acids also certainly play a role in the establishment of membrane-less organelles enriched in RNA and RNA-binding proteins [55,62]. In agreement with the importance of electrostatic interactions between macromolecules with different charges, phosphorylation and acetylation have been shown to perturb phase separation and dissolve membrane-less organelles [62][63][64][65]. Hydrophobic interactions have also been suggested to play an important role in phase separation [35,66].…”

Section: The Physical Properties Of Phase Separation and Heterochromatinmentioning

confidence: 96%

“…Modifying relevant serines and threonines to glutamic acid, which mimics phosphorylation, is also another means of the disturbing phase separation [64,93]. Acetylation of intrinsically disordered regions has also been shown to regulate phase separation [65] and mimicking acetylation may provide additional experimental strategies. Finally, it is important to note that we have not considered a possible role for RNA interactions in this current work.…”

Section: Current In Vivo Assays To Address Phase Separation In Heteromentioning

confidence: 99%

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Expression and phase separation potential of heterochromatin proteins during early mouse development

2019

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In most eukaryotes, constitutive heterochromatin is associated with H3K9me3 and HP1α. The latter has been shown to play a role in heterochromatin formation through liquid–liquid phase separation. However, many other proteins are known to regulate and/or interact with constitutive heterochromatic regions in several species. We postulate that some of these heterochromatic proteins may play a role in the regulation of heterochromatin formation by liquid–liquid phase separation. Indeed, an analysis of the constitutive heterochromatin proteome shows that proteins associated with constitutive heterochromatin are significantly more disordered than a random set or a full nucleome set of proteins. Interestingly, their expression begins low and increases during preimplantation development. These observations suggest that the preimplantation embryo is a useful model to address the potential role for phase separation in heterochromatin formation, anticipating exciting research in the years to come.

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Section: The Physical Properties Of Phase Separation and Heterochromatinmentioning

confidence: 96%

Section: Current In Vivo Assays To Address Phase Separation In Heteromentioning

confidence: 99%

Expression and phase separation potential of heterochromatin proteins during early mouse development

2019

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“…Lastly, the DEAD‐box RNA helicase DDX3X is a SG protein that is frequently mutated in various cancers including pediatric and adult medulloblastomas. Both the helicase core of DDX3X (mediating RNA binding) and N‐terminal IDRs (mediating DDX3X phase separation) contribute to its partitioning into SGs . Cancer‐associated DDX3X mutations are mostly found in the helicase core and induce SG assembly in an eIF2a‐independent manner, possibly by inhibiting the translational activity of DDX3X .…”

Section: Biomolecular Condensates In Cancermentioning

confidence: 99%

Biomolecular condensates in neurodegeneration and cancer

Spannl

Tereshchenko

Mastromarco

et al. 2019

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The intracellular environment is partitioned into functionally distinct compartments containing specific sets of molecules and reactions. Biomolecular condensates, also referred to as membrane‐less organelles, are diverse and abundant cellular compartments that lack membranous enclosures. Molecules assemble into condensates by phase separation; multivalent weak interactions drive molecules to separate from their surroundings and concentrate in discrete locations. Biomolecular condensates exist in all eukaryotes and in some prokaryotes, and participate in various essential house‐keeping, stress‐response and cell type‐specific processes. An increasing number of recent studies link abnormal condensate formation, composition and material properties to a number of disease states. In this review, we discuss current knowledge and models describing the regulation of condensates and how they become dysregulated in neurodegeneration and cancer. Further research on the regulation of biomolecular phase separation will help us to better understand their role in cell physiology and disease.

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“…SG assembly is regulated positively and negatively by post-translational modifications of proteins, including those that conjugate simple chemical groups (such as phosphorylation, O-GlcNAc glycosylation, methylation, acetylation), attach polypeptides (e.g., neddylation), and add nucleotides as in the case of ADP-ribosylation [15][16][17][18][19][20][21]. ADP-ribosylation refers to the addition of one or more ADP-Page 4 ribose units onto proteins [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulation of SG assembly/disassembly and mutations in the low-complexity region of specific SG proteins are implicated in the pathogenesis of diseases such as viral infection, cancer and neurodegeneration [1,[12][13][14]. Therefore, understanding the regulatory mechanisms of SG assembly is critical for designing novel therapeutics.SG assembly is regulated positively and negatively by post-translational modifications of proteins, including those that conjugate simple chemical groups (such as phosphorylation, O-GlcNAc glycosylation, methylation, acetylation), attach polypeptides (e.g., neddylation), and add nucleotides as in the case of ADP-ribosylation [15][16][17][18][19][20][21]. ADP-ribosylation refers to the addition of one or more ADP-Page 4 ribose units onto proteins [22][23][24].…”

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confidence: 99%

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

Jayabalan

Griffin

Leung

2019

Preprint

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Formation of stress granules (SGs), cytoplasmic condensates of stalled translation initiation complexes, is regulated by post-translational protein modification. Alphaviruses interfere with SG formation in response to inhibition of host protein synthesis through the activities of nonstructural protein 3 (nsP3). nsP3 has a conserved N-terminal macrodomain that binds and can remove ADP-ribose from ADPribosylated proteins and a C-terminal hypervariable domain that binds essential SG component G3BP1.We showed that the hydrolase activity of chikungunya virus nsP3 macrodomain removed ADPribosylation of G3BP1 and suppressed SG formation. ADP-ribosylhydrolase-deficient nsP3 mutants allowed stress-induced cytoplasmic condensation of translation initiation factors. nsP3 also disassembled SG-like aggregates enriched with translation initiation factors that are induced by the expression of FUS mutant R495X linked to amyotrophic lateral sclerosis. Therefore, our data indicate that regulation of ADP-ribosylation controls the localization of translation initiation factors during virus infection and other pathological conditions. All rights reserved. No reuse allowed without permission. INTRODUCTIONNon-membranous structures are prevalent in cells and critical for cellular functions, including RNA metabolism, embryonic cell fate specification, and neuronal activities [1][2][3]. Although the components of these non-membranous structures are often dynamically exchanged with the surrounding milieu, the compositions of these cellular structures remain distinct [4]. It is, however, unclear how individual components are selectively retained in these non-membranous structures.Stress granules (SGs), one of the best characterized dynamic non-membranous structures, are RNAprotein assemblies formed in response to a variety of environmental cues [3]. In most cases, these environmental cues activate stress-responsive protein kinases that phosphorylate the eukaryotic initiation factor 2 alpha (eIF2α), resulting in the stalling of translation initiation [3]. The sudden influx of untranslated mRNAs is proposed to seed the formation of SGs, where the polynucleotide promotes local concentration of proteins through non-covalent binding [5]. These RNA-binding proteins are highly enriched with low-complexity regions, and emergent data indicate that the nonspecific, weak interactions between these regions are responsible for the condensation of proteins to form higherorder structures, such as microscopically visible SGs [6][7][8]. Depending on the type of stress, the composition of SGs could vary [9], but certain common components, such as Ras GTP-activating protein-binding proteins G3BP1/2, are essential for SG formation [10,11]. Dysregulation of SG assembly/disassembly and mutations in the low-complexity region of specific SG proteins are implicated in the pathogenesis of diseases such as viral infection, cancer and neurodegeneration [1,[12][13][14]. Therefore, understanding the regulatory mechanisms of SG assembly is critical for designing novel th...

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Acetylation of intrinsically disordered regions regulates phase separation

Cited by 217 publications

References 57 publications

Expression and phase separation potential of heterochromatin proteins during early mouse development

Expression and phase separation potential of heterochromatin proteins during early mouse development

Biomolecular condensates in neurodegeneration and cancer

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

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