Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation

Petrovska, Ivana; Nüske, Elisabeth; Munder, Matthias C.; Kulasegaran, Gayathrie; Malinovska, Liliana; Kroschwald, Sonja; Richter, Doris; Fahmy, Karim; Gibson, Kimberley; Verbavatz, Jean‐Marc; Alberti, Simon

doi:10.7554/elife.02409

Cited by 194 publications

(131 citation statements)

References 54 publications

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“…The presence of CTPS-containing filamentous structures across diverse species suggests that cytoophidium formation is likely to have an important biological function and may represent a common regulatory strategy for the production of CTP and other nucleotides in the cell (Ingerson-Mahar et al 2010;Liu 2010Liu , 2011Noree et al 2010). Indeed, recent studies have shown that cytoophidia are dynamic structures that respond to metabolic state and external cues such as stress (Aughey et al 2014, Barry et al 2014, Noree et al 2014, Petrovska et al 2014). The compartmentation of metabolic enzymes such as CTPS and IMPDH into these filamentous structures, therefore, presents a convenient model to study the cellular mechanisms responsible for enzyme sequestration into cytoplasmic filaments and to elucidate their significance.…”

Section: Discussionmentioning

confidence: 95%

“…Glutamine synthase was initially identified as a foci-forming protein that was incapable of forming filaments under standard culture conditions. However, a study by the Alberti group showed that low pH can induce glutamine synthase to form filaments, which in turn inactivate enzymatic activity (Petrovska et al 2014). This group also demonstrated that filamentation of CTPS is sensitive to pH change, suggesting that filamentation is a general mechanism to regulate enzymatic activity.…”

Section: Foci Versus Filamentsmentioning

confidence: 96%

“…The dependence of cytoophidium assembly on CTP levels provides another explanation (Barry et al 2014). Nutrient stress, such as glutamine deprivation or glucose starvation, promotes cytoophidium assembly (Aughey et al 2014, Noree et al 2010, Petrovska et al 2014. In budding yeast, removing glucose from the media results in more cells having cytoophidia (Noree et al 2010).…”

Section: Compartmentation For Metabolic Regulationmentioning

confidence: 98%

“…Abnormal metabolism contributes to disorders such as cancer, diabetes, and obesity. Several groups have recently demonstrated that compartmentation via filamentation of the metabolic enzymes provides a novel mechanism for regulation of metabolic processes (Aughey et al 2014, Barry et al 2014, Noree et al 2014, Petrovska et al 2014, Strochlic et al 2014. Cytoophidium formation facilitates metabolic stabilization.…”

Section: Compartmentation For Metabolic Regulationmentioning

confidence: 99%

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The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes

Liu

2016

Annu. Rev. Cell Dev. Biol.

114

109

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Compartmentation is essential for the localization of biological processes within a cell. In 2010, three groups independently reported that cytidine triphosphate synthase (CTPS), a metabolic enzyme for de novo synthesis of the nucleotide CTP, is compartmentalized in cytoophidia (Greek for "cellular snakes") in bacteria, yeast, and fruit flies. Subsequent studies demonstrate that CTPS can also form filaments in human cells. Thus, the cytoophidium represents a new type of intracellular compartment that is strikingly conserved across prokaryotes and eukaryotes. Multiple lines of evidence have recently suggested that polymerization of metabolic enzymes such as CTPS and inosine monophosphate dehydrogenase into filamentous cytoophidia modulates enzymatic activity. With many more metabolic enzymes found to form the cytoophidium and its kind, compartmentation via filamentation may serve as a general mechanism for the regulation of metabolism.

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Section: Discussionmentioning

confidence: 95%

Section: Foci Versus Filamentsmentioning

confidence: 96%

Section: Compartmentation For Metabolic Regulationmentioning

confidence: 98%

Section: Compartmentation For Metabolic Regulationmentioning

confidence: 99%

See 2 more Smart Citations

The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes

Liu

2016

Annu. Rev. Cell Dev. Biol.

114

109

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“…More important is whether a distinct functional consequence can be attributed to the prion-like state. Many cellular proteins form aggregates/oligomers to serve their normal functions (Brangwynne et al 2009, Kwon et al 2013, Lee et al 2013, Malinovska et al 2013, Petrovska et al 2014. Some of the oligomers are stable, though they are not amyloids, whereas other protein assemblies are labile but possess features of amyloids.…”

Section: Examples Of Functional Prionsmentioning

confidence: 99%

Prions: What Are They Good For?

2015

Annu. Rev. Cell Dev. Biol.

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Prions, a self-templating amyloidogenic state of normal cellular proteins such as PrP, have been identified as the basis of a number of disease states, particularly diseases of the nervous system. This finding has led to the notion that protein aggregation, namely prionogenic aggregates and amyloids, is primarily harmful for the organism. However, identification of proteins in a prion-like state that are not harmful and may even be beneficial has begun to change this perception. This review discusses when and how a prion-based protein conformational switch may be utilized to generate a sustained physiological change in response to a transient stimulus.

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Protein Condensation, Cellular Organization, and Spatiotemporal Regulation of Cytoplasmic Properties

Tartwijk

Kaminski

2022

Advanced Biology

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These folds are determined by both protein sequence and solvent properties, and determine protein function. [2] Therefore, the diversity of protein folds in cells allows them to carry out a range of functions, such as catalysis of different reactions. Functional versatility within polypeptide chains is further increased through the presence of multiple independently folding sequences, defined as domains, each associated with distinct functions, such as dimerization or responsiveness to a regulator. However, it is now recognized that some proteins do not have defined conformations, or feature domains that are intrinsically disordered (intrinsically disordered regions, IDRs), and that these confer function by mediating context-dependent proteinprotein interactions. [3] The concept of self-organization of proteins is also applied to assemblies of multiple proteins, in which case it refers to formation of dynamic multi-component structures, [4] including certain oligomeric complexes, filaments, and phase-separated assemblies. In phase-separated assemblies, of which a range exist, IDR-containing proteins form a dense phase within the cytoplasm, commonly referred to as biomolecular condensates. [5] As for folds, the formation of these assemblies depends both on interactions between the phase-separating proteins, which can be mediated by their IDRs, and between these proteins and the surrounding solution. Within the cytoplasm, these phase-separated "droplets" commonly contain RNA, in which case they are referred to as ribonucleoprotein (RNP) granules. They can be considered to have "emergent properties:" certain characteristics can be ascribed to assemblies that are not properties of individual constituent proteins. [6] For instance, biomolecular condensates can display liquid-like properties such as fusion and wetting, which led to their identification as phase-separated droplets. [7] These properties allow them to function as dynamic membraneless organelles, or compartments. This compartmentalization is commonly referred to as occurring on the "mesoscale," which is defined as that range of lengths larger than the size of individual molecular machinery such as ribosomes, but smaller than that of the whole cell. [8] The sensitivity of protein folds and macromolecular interactions to local environmental conditions confers both regulatory potential and risk of loss of function in "extreme" conditions. This regulatory potential is exemplified by and has beenThe cytoplasm is an aqueous, highly crowded solution of active macromolecules. Its properties influence the behavior of proteins, including their folding, motion, and interactions. In particular, proteins in the cytoplasm can interact to form phase-separated assemblies, so-called biomolecular condensates. The interplay between cytoplasmic properties and protein condensation is critical in a number of functional contexts and is the subject of this review. The authors first describe how cytoplasmic properties can affect protein behavior, in particular condensate formation...

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Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation

Cited by 194 publications

References 54 publications

The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes

The Cytoophidium and Its Kind: Filamentation and Compartmentation of Metabolic Enzymes

Prions: What Are They Good For?

Protein Condensation, Cellular Organization, and Spatiotemporal Regulation of Cytoplasmic Properties

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