As a toxin dies a prion comes to life: A tentative natural history of the [Het-s] prion

Daskalov, Asen; Saupe, Sven J.

doi:10.1080/19336896.2015.1038018

Cited by 19 publications

(16 citation statements)

References 35 publications

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“…In this context, allorecognition systems in fungi have been proposed to originate from broader pathways, evolutionarily related to innate immunity systems of plants and animals ( 14 , 35 , 36 ). It has been speculated that emergence of such allorecognition systems is due to sporadic mutations and subsequent cooptation of genes evolved primarily to mediate heterospecific nonself recognition and detection of modified self ( 37 , 38 ). The rcd-1 locus has undergone extensive genomic rearrangements in the genus Neurospora , which have been proposed to be at the origin of the allorecognition system ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of a fungal gasdermin-like protein

Daskalov

Mitchell

Sandstrom

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Programmed cell death (PCD) in filamentous fungi prevents cytoplasmic mixing following fusion between conspecific genetically distinct individuals (allorecognition) and serves as a defense mechanism against mycoparasitism, genome exploitation, and deleterious cytoplasmic elements (i.e., senescence plasmids). Recently, we identified regulatorof cell death-1 (rcd-1), a gene controlling PCD in germinated asexual spores in the filamentous fungus Neurospora crassa. rcd-1 alleles are highly polymorphic and fall into two haplogroups in N. crassa populations. Coexpression of alleles from the two haplogroups, rcd-1–1 and rcd-1–2, is necessary and sufficient to trigger a cell death reaction. Here, we investigated the molecular bases of rcd-1-dependent cell death. Based on in silico analyses, we found that RCD-1 is a remote homolog of the N-terminal pore-forming domain of gasdermin, the executioner protein of a highly inflammatory cell death reaction termed pyroptosis, which plays a key role in mammalian innate immunity. We show that RCD-1 localizes to the cell periphery and that cellular localization of RCD-1 was correlated with conserved positively charged residues on predicted amphipathic α-helices, as shown for murine gasdermin-D. Similar to gasdermin, RCD-1 binds acidic phospholipids in vitro, notably, cardiolipin and phosphatidylserine, and interacts with liposomes containing such lipids. The RCD-1 incompatibility system was reconstituted in human 293T cells, where coexpression of incompatible rcd-1–1/rcd-1–2 alleles triggered pyroptotic-like cell death. Oligomers of RCD-1 were associated with the cell death reaction, further supporting the evolutionary relationship between gasdermin and rcd-1. This report documents an ancient transkingdom relationship of cell death execution modules involved in organismal defense.

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of a fungal gasdermin-like protein

Daskalov

Mitchell

Sandstrom

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Yet, except in the specific case of NLRs involved in incompatibility systems the nature of the ligands activating these NLRs are currently unknown. Compared to the two other systems, the NWD2/HET-S is characterized by the fact that this system has been exaptated as an allorecognition system in [Het-s]/HET-S incompatibility [36]. It has been possible experimentally, to derive incompatibility systems analogous to [Het-s]/HET-S from both HELLP and HELLF.…”

Section: Discussionmentioning

confidence: 99%

Partial prion cross-seeding between fungal and mammalian amyloid signaling motifs

Bardin

Daskalov

Barrouilhet

et al. 2020

Preprint

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In fungi, NLR-based signalosomes activate downstream membrane-targeting cell-death inducing proteins by a mechanism of amyloid templating. In the species Podospora anserina, two such signalosomes, NWD2/HET-S and FNT1/HELLF have been described as well as an analogous system, involving a distinct amyloid signaling motif termed PP in the species Chaetomium globosum. The PP-motif bears resemblance to the RHIM and RHIM-like motifs controlling necroptosis in mammals and innate immunity in Drosophila. We identified here, a third NLR signalosome in Podospora anserina comprising a PP-motif and organized as a two-gene cluster encoding a NLR and a HELL-domain cell-death execution protein termed HELLP. We show that the PP-motif region of HELLP forms a prions we term [π] and that [π] prions trigger the cell-death inducing activity of full length HELLP. We detect no prion cross-seeding between HET-S, HELLF and HELLP amyloid motifs. In addition, we find that akin to PP-motifs, RHIM motifs from human RIP1 and RIP3 kinases are able to form prions in Podospora, and that [π] and [Rhim] prions cross-seed. Our study shows Podospora display three independent amyloid signalosomes. Based on the described functional similarity between RHIM and PP it appears likely that these amyloid motifs constitute evolutionary related cell-death signaling modules.Author summaryAmyloids are fibrillar protein polymers assembled from cross β-sheets. Pathogenic amyloids are responsible for a range of neuronal and systemic protein misfolding diseases. In addition, functional amyloids fulfill a variety of biological functions in microbes and animals. In fungi, amyloids control prion-like signaling pathways with roles in host defense and immune programmed cell death. These signaling pathways involve a Nod-like receptor and a cell-death execution protein activated through amyloid templating. In P. anserina two such amyloid signaling systems were identified so far. Here we identified and characterized a third amyloid signaling system comprising a different amyloid motif termed PP. We showed a total absence of cross-induction between the three P. anserina systems allowing for the co-existence of three independent amyloid signaling cascades in the same organism. An evolutionary relationship between fungal amyloid motifs and mammalian RHIM amyloid motif involved in the necroptosis pathway was previously suggested. We validated this assumption by showing that the human RHIM motif could not only propagate as a prion in P. anserina but also functionally cross-interact with the fungal PP-motif prions. These results point to a long term evolutionary conservation of amyloid signaling mechanisms from fungi to mammals.

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“…HET-s and HET-S functionally differ in their HeLo domain, a substitution at position 33 deprives HET-S of pore-forming activity. In a sense HET-s can be viewed as a mutant form of HET-S devoid of cell death inducing activity, it is that very property (lack of toxicity associated with the amyloid form) that allows the protein to propagate as a prion in vivo [ 21 ].…”

Section: The Het-s/het-s Systemmentioning

confidence: 99%

“…Note that the incompatibility reaction between [Het-s] and HET-S occurs independently of NWD2. Incompatibility is proposed to derive by exaptation from the NWD2/HET-S system, yet it does not require NWD2 to occur [ 21 ]. Remarkably, it was reported that the N-terminal region of NWD2 and the HET-s PFD can functionally substitute for the Pyrin signaling domains in the human NLRP3 NLR and ASC, its downstream effector.…”

Section: The Nwd2/het-s Paradigmmentioning

confidence: 99%

Diversity of Amyloid Motifs in NLR Signaling in Fungi

Loquet

Saupe

2017

Biomolecules

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Amyloid folds not only represent the underlying cause of a large class of human diseases but also display a variety of functional roles both in prokaryote and eukaryote organisms. Among these roles is a recently-described activity in signal transduction cascades functioning in host defense and programmed cell death and involving Nod-like receptors (NLRs). In different fungal species, prion amyloid folds convey activation signals from a receptor protein to an effector domain by an amyloid templating and propagation mechanism. The discovery of these amyloid signaling motifs derives from the study of [Het-s], a fungal prion of the species Podospora anserina. These signaling pathways are typically composed of two basic components encoded by adjacent genes, the NLR receptor bearing an amyloid motif at the N-terminal end and a cell death execution protein with a HeLo pore-forming domain bearing a C-terminal amyloid motif. Activation of the NLR receptor allows for amyloid folding of the N-terminal amyloid motifs which then template trans-conformation of the homologous motif in the cell death execution protein. A variety of such motifs, which differ by their sequence signature, have been described in fungi. Among them, the PP-motif bears resemblance with the RHIM amyloid motif involved in the necroptosis pathway in mammals suggesting an evolutionary conservation of amyloid signaling from fungi to mammals.

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As a toxin dies a prion comes to life: A tentative natural history of the [Het-s] prion

Cited by 19 publications

References 35 publications

Molecular characterization of a fungal gasdermin-like protein

Molecular characterization of a fungal gasdermin-like protein

Partial prion cross-seeding between fungal and mammalian amyloid signaling motifs

Diversity of Amyloid Motifs in NLR Signaling in Fungi

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