It Pays To Be in Phase

Itakura, Alan K.; Futia, Raymond A.; Jarosz, Daniel F.

doi:10.1021/acs.biochem.8b00205

Cited by 33 publications

(30 citation statements)

References 120 publications

(341 reference statements)

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“…The general consensus in the field is that membraneless organelles are formed by phase separation of their components from the surrounding nucleo‐ or cytoplasm . Phase separation defines the behavior of a seemingly homogeneous solution of diffuse macromolecules that segregate into two distinct phases that then stably coexist .…”

Section: An Overview Of Mechanisms Driving Formation Of Membraneless mentioning

confidence: 99%

Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells

Rabouille

2019

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In cells at steady state, two forms of cell compartmentalization coexist: membrane‐bound organelles and phase‐separated membraneless organelles that are present in both the nucleus and the cytoplasm. Strikingly, cellular stress is a strong inducer of the reversible membraneless compartments referred to as stress assemblies. Stress assemblies play key roles in survival during cell stress and in thriving of cells upon stress relief. The two best studied stress assemblies are the RNA‐based processing‐bodies (P‐bodies) and stress granules that form in response to oxidative, endoplasmic reticulum (ER), osmotic and nutrient stress as well as many others. Interestingly, P‐bodies and stress granules are heterogeneous with respect to both the pathways that lead to their formation and their protein and RNA content. Furthermore, in yeast and Drosophila, nutrient stress also leads to the formation of many other types of prosurvival cytoplasmic stress assemblies, such as metabolic enzymes foci, proteasome storage granules, EIF2B bodies, U‐bodies and Sec bodies, some of which are not RNA‐based. Nutrient stress leads to a drop in cytoplasmic pH, which combined with posttranslational modifications of granule contents, induces phase separation.

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Section: An Overview Of Mechanisms Driving Formation Of Membraneless mentioning

confidence: 99%

Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells

Rabouille

2019

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“…Many membraneless organelles including nuclear assemblies such as PML NBs, Cajal bodies, and nuclear speckles represent biomolecular condensates (BMCs) formed through LLPS. Their formation is thought to be driven by transient protein-protein or protein-nucleic acid interactions, and it can be facilitated by the intrinsically disordered regions (IDRs) of proteins [87][88][89][90].…”

Section: Biophysical Processes In Replication Compartment Formationmentioning

confidence: 99%

“…For example, many viral proteins including VRC proteins contain either predicted or experimentally validated IDRs [96][97][98][99][100][101]. In many cases, the accumulation of these viral proteins throughout the nucleoplasm can be detected prior to the formation of VRCs [16,68,85], suggesting that their formation is concentration dependent, which is another feature of LLPS [87][88][89][90]. HSV-1, CMV, PRV, and HAdV VRCs also coalesce as infection progresses and they grow, fusing together in a liquid-like manner [14,15,61,62,65,69,95,[102][103][104].…”

Section: Biophysical Processes In Replication Compartment Formationmentioning

confidence: 99%

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Charman

Weitzman

2020

Viruses

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DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus-host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses.Viruses 2020, 12, 151 2 of 20 The Initiation and Formation of Replication CompartmentsDNA viruses that replicate in the nucleus exhibit a diverse array of strategies to complete their replication cycle and ultimately produce progeny virions. Despite their many differences, the strategies employed by DNA viruses to initiate productive infection and establish VRCs share many features in common. Indeed, it is likely that all DNA viruses that replicate in the nucleus form VRCs. Following penetration of the host cell and the transport of viral capsids/cores, viral DNA genomes enter the nucleus, where they begin a program of temporally regulated gene expression that initiates productive infection [1,2]. Early gene products include viral proteins required to manipulate the host-cell environment and replicate the viral genome. Viral replication proteins interact with the viral genome and initiate genome replication leading to VRC formation, which is often in concert with certain co-opted host proteins. However, these viruses must overcome several challenges to form VRCs successfully. Firstly, incoming genomes must avoid cellular intrinsic antiviral defenses and homeostatic regulatory pathways such as elements of the DNA damage response (DDR) that respond to the presence of foreign DNA and act to suppress viral gene expression [3][4][5][6][7][8][9][10]. Secondly, VRCs typically form at specific sites within the nucleus, suggesting that viral genomes need to be targeted to these sites in order to initiate VRC formation [6,11,12]. Furthermore, it has been hypothesized that the formation and growth of VRCs may require manipulation of the nuclear environment and the re-organization of host chromatin to overcome the spatial restraints of the nucleus [11][12][13][14][15]. In this section, we review key features of VRC initiation and highlight some major challenges to VRC formation. Interplay between Viral Replication Compartment Formation and Promyelocytic Leukemia Protein Nuclear BodiesA common theme amongst many nuclear-replicating DNA viruses is initiation of VRCs at sites in close proximity to promyelocytic leukemia protein (PML) nuclear bodies (NBs). Since the dis...

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“…In vitro reconstitution experiments also helped to establish that biological phase separation is mainly driven by weak promiscuous interactions between multivalent protein interaction domains (8) or intrinsically disordered low complexity domains (LCDs) (17). As multivalent interaction motifs and short linear motifs in intrinsically disordered regions (IDRs) and LCDs are often post-translationally modified (18 -21), it is not surprising that post-translational modifications (PTMs) are important regulators of phase separation (22,23). PTMs change the physico-chemical properties of the modified amino acids, e.g.…”

mentioning

confidence: 99%

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

Hofweber¹,

Dormann

2019

Journal of Biological Chemistry

306

294

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Edited by Paul E. FraserRibonucleoprotein (RNP) granules are membrane-less organelles consisting of RNA-binding proteins (RBPs) and RNA. RNA granules form through liquid-liquid phase separation (LLPS), whereby weak promiscuous interactions among RBPs and/or RNAs create a dense network of interacting macromolecules and drive the phase separation. Post-translational modifications (PTMs) of RBPs have emerged as important regulators of LLPS and RNP granule dynamics, as they can directly weaken or enhance the multivalent interactions between phase-separating macromolecules or can recruit or exclude certain macromolecules into or from condensates. Here, we review recent insights into how PTMs regulate phase separation and RNP granule dynamics, in particular arginine (Arg)-methylation and phosphorylation. We discuss how these PTMs regulate the phase behavior of prototypical RBPs and how, as "friend or foe," they might influence the assembly, disassembly, or material properties of cellular RNP granules, such as stress granules or amyloidlike condensates. We particularly highlight how PTMs control the phase separation and aggregation behavior of disease-linked RBPs. We also review how disruptions of PTMs might be involved in aberrant phase transitions and the formation of amyloid-like protein aggregates as observed in neurodegenerative diseases.

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It Pays To Be in Phase

Cited by 33 publications

References 120 publications

Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells

Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

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