A Non-amyloid Prion Particle that Activates a Heritable Gene Expression Program

Chakravarty, Anupam K.; Smejkal, Tina; Itakura, Alan K.; Garcia, David M; Jarosz, Daniel F.

doi:10.1016/j.molcel.2019.10.028

Cited by 71 publications

(69 citation statements)

References 141 publications

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“…Confirming their presence would indicate their existence in all three domains of life, suggesting that prions were likely present during the time of LUCA. Though many prions do not form amyloid (73)(74)(75), in the current study we focused on amyloidforming cPrDs because recently identified bacterial prions have been shown to form amyloids (45), and amyloid fibril formation can also be detected with a relatively high-throughput experimental survey like the Congo red assay used here. We utilized the computational program PLAAC (49) to identify novel cPrDs.…”

Section: Discussionmentioning

confidence: 99%

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

Zajkowski

Lee

Mondal

et al. 2020

Preprint

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Prions are proteins capable of acquiring an alternate conformation that can then induce additional copies to adopt this same alternate conformation. Although initially discovered in relation to mammalian disease, subsequent studies have revealed the presence of prions in Bacteria and Viruses, suggesting an ancient evolutionary origin. Here we explore whether prions exist in Archaea - the last domain of life left unexplored with regard to prions. After searching for potential prion-forming protein sequences computationally, we tested candidates in vitro and in organisms from the two other domains of life: Escherichia coli and Saccharomyces cerevisiae. Out of the 16 candidate prion-forming domains tested, 8 bound to amyloid-specific dye, and six acted as protein-based elements of information transfer, driving non-Mendelian patterns of inheritance. We additionally identified short peptides from archaeal prion candidates that can form amyloid fibrils independently. Candidates that tested positively in our assays had significantly higher tyrosine and phenylalanine content than candidates that tested negatively, suggesting that the presence of these amino acids may help distinguish functional prion domains from nonfunctional ones. Our data establish the presence of amyloid-forming prion-like domains in Archaea. Their discovery in all three domains of life further suggests the possibility that they were present at the time of the last universal common ancestor (LUCA).Significance StatementThis work establishes that amyloid-forming, prion-like domains exist in Archaea and are capable of vertically transmitting their prion phenotype – allowing them to function as protein-based elements of inheritance. These observations, coupled with prior discoveries in Eukarya and Bacteria, suggest that prion-based self-assembly was likely present in life’s last universal common ancestor (LUCA), and therefore may be one of the most ancient epigenetic mechanisms.

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Section: Discussionmentioning

confidence: 99%

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

Zajkowski

Lee

Mondal

et al. 2020

Preprint

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“…The role of Smaug orthologues as post-transcriptional regulators of energetic metabolism appears evolutionary conserved as yeast Vts1p –which forms MLOs and prion-like condensates– controls mRNAs linked to nutrient sensing (Chakravarty et al, 2020; She et al, 2017). Translation of nuclear-encoded transcripts at the mitochondrial periphery is known to be regulated by a reduced number of RNA-binding proteins, including the highly conserved factors clustered mitochondria homolog (CLUH) and Pumilio orthologs (reviewed in(D’Amico et al, 2019; Gao et al, 2014; Gehrke et al, 2015; Kopp et al, 2019; Lee & Tu, 2015; Olivas & Parker, 2000; Pla-Martin et al, 2020; Schatton et al, 2017; Schatton & Rugarli, 2018; Vardi-Oknin & Arava, 2019; Wakim et al, 2017) The putative interplay between these pathways and Smaug remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular consequences of Smaug-body formation are incipiently described. Condensation of the yeast ortholog Vts1 facilitates the degradation of target mRNAs (Chakravarty et al, 2020), whereas mammalian Smaug1-body dissolution is linked to mRNA release and translational activation of dendritic mRNAs (Baez et al, 2011; Luchelli et al, 2015). The formation of MLOs and related molecular condensates is thought to involve liquid-liquid phase separation (LLPS) processes driven by multiple protein-protein interactions, which remain unknown in the case of Smaug (Courchaine et al, 2016; Guo & Shorter, 2015; Perez-Pepe et al, 2018; Sachdev et al, 2019; Van Treeck et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Finally, a point mutation in murine Smaug1 generates a complex phenotype characterized by leanness, resistance to fat intake-induced obesity, reduced muscle and adipose tissue, and abnormal morphology of both myofibers and adipocytes (Chen, Holland, et al, 2014). Work in yeast showed that Vts1 is involved in nutrient sensing (Chakravarty et al, 2020; She et al, 2017) and thus, a connection between Smaug and the energetic metabolism appears conserved from yeast to animals.…”

Section: Introductionmentioning

confidence: 99%

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Smaug membraneless organelles regulate mitochondrial function

Fernández-Alvarez

Thomas

Pascual

et al. 2020

Preprint

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Smaug is a conserved translational repressor that recognizes specific RNA motifs in a large number of mRNAs, including nuclear transcripts that encode mitochondrial enzymes. Smaug orthologs have been shown to form membraneless organelles (MLOs) in several organisms and cell types. Using single-molecule FISH we show here that SDHB and UQCRC1 mRNAs associate with Smaug1 MLOs in the human cell line U2OS. Simultaneous loss of function of Smaug1 and Smaug2 affects both mitochondrial respiration and mitochondrial network morphology. Deletion of specific Smaug1 protein regions resulted in impaired MLO formation that correlates with mitochondrial defects. In addition, rotenone but not the respiratory chain uncoupling agent CCCP rapidly induces Smaug1 MLO dissolution. Finally, metformin elicits a similar effect on Smaug1 MLOs and provokes the release of bounded mRNAs. We propose that mitochondrial activity affects Smaug1 MLO dynamics, thus allowing for regulation of nuclear mRNAs that encode key mitochondrial proteins.

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“…The case of prion [␤] argues for omitting the amyloid formation from the list of essential properties of a prion. Two other recently described yeast prions, [SMAUGϩ], the product of the Vts1 gene, and [ESIϩ], the product of the Snt1 gene, also do not appear to form amyloids, though both may form other kinds of aggregates (26,27).…”

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confidence: 99%

RNAs That Behave Like Prions

Mushegian

Elena

2020

mSphere

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The term “prion” was originally coined to describe the proteinaceous infectious agents involved in mammalian neurological disorders. More recently, a prion has been defined as a nonchromosomal, protein-based genetic element that is capable of converting the copies of its own benign variant into the prion form, with the new phenotypic effects that can be transmitted through the cytoplasm. Some prions are toxic to the cell, are able to aggregate and/or form amyloid structures, and may be infectious in the wild, but none of those traits are seen as an integral property of all prions. We propose that the definition of prion should be expanded, to include the inducible transmissible entities undergoing autocatalytic conversion and consisting of RNA rather than protein. We show that when seen in this framework, some naturally occurring RNAs, including ribozymes, riboswitches, viroids, viroid-like retroelements, and PIWI-interacting RNAs (piRNAs), possess several of the characteristic properties of prions.

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A Non-amyloid Prion Particle that Activates a Heritable Gene Expression Program

Abstract: Highlights d The Vts1 IDR promotes its condensation into the non-amyloid prion [SMAUG + ] d [SMAUG + ] hyperactivates Vts1 function d [SMAUG + ] rewires post-transcriptional gene regulation to promote proliferation d Self-assembly is conserved in the human Vts1 homolog hSmaug1

Cited by 71 publications

References 141 publications

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

Smaug membraneless organelles regulate mitochondrial function

RNAs That Behave Like Prions

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