title: Identification of a novel cell death-inducing domain reveals that fungal amyloid-controlled programmed cell death is related to necroptosis.
abstract: Recent findings have revealed the role of prion-like mechanisms in the control of host defense and programmed cell death cascades. In fungi, HET-S, a cell death-inducing protein containing a HeLo pore-forming domain, is activated through amyloid templating by a Nod-like receptor (NLR). Here we characterize the HELLP protein behaving analogously to HET-S and bearing a new type of N-terminal cell death-inducing domain termed HeLo-like (HELL) and a C-terminal regulatory amyloid motif known as PP. The gene encoding HELLP is part of a three-gene cluster also encoding a lipase (SBP) and a Nod-like receptor, both of which display the PP motif. The PP motif is similar to the RHIM amyloid motif directing formation of the RIP1/RIP3 necrosome in humans. The C-terminal region of HELLP, HELLP(215-278), encompassing the motif, allows prion propagation and assembles into amyloid fibrils, as demonstrated by X-ray diffraction and FTIR analyses. Solid-state NMR studies reveal a well-ordered local structure of the amyloid core residues and a primary sequence that is almost entirely arranged in a rigid conformation, and confirm a β-sheet structure in an assigned stretch of three amino acids. HELLP is activated by amyloid templating and displays membrane-targeting and cell death-inducing activity. HELLP targets the SBP lipase to the membrane, suggesting a synergy between HELLP and SBP in membrane dismantling. Remarkably, the HeLo-like domain of HELLP is homologous to the pore-forming domain of MLKL, the cell death-execution protein in necroptosis, revealing a transkingdom evolutionary relationship between amyloid-controlled fungal programmed cell death and mammalian necroptosis.
authors.affiliation: Institut de Biochimie et de Génétique Cellulaire, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Asen
authors.initials: A
authors.lastname: Daskalov
authors.affiliation: Institut de Chimie et Biologie des Membranes et des Nanoobjets, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Birgit
authors.initials: B
authors.lastname: Habenstein
authors.affiliation: Institut de Nanociència i Nanotecnologia, Departament Fisicoquímica, Universitat de Barcelona, E-08028 Barcelona, Spain;
authors.forename: Raimon
authors.initials: R
authors.lastname: Sabaté
authors.affiliation: Institut de Chimie et Biologie des Membranes et des Nanoobjets, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Mélanie
authors.initials: M
authors.lastname: Berbon
authors.affiliation: Institut de Chimie et Biologie des Membranes et des Nanoobjets, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Denis
authors.initials: D
authors.lastname: Martinez
authors.affiliation: Institut de Biochimie et de Génétique Cellulaire, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chaignepain
authors.affiliation: Institut de Biochimie et de Génétique Cellulaire, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Coulary-Salin
authors.affiliation: Institute for Genetics, University of Cologne, D-50674 Cologne, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.affiliation: Institut de Chimie et Biologie des Membranes et des Nanoobjets, CNRS, Université de Bordeaux, 33077 Bordeaux, France;
authors.forename: Antoine
authors.initials: A
authors.lastname: Loquet
authors.affiliation: Institut de Biochimie et de Génétique Cellulaire, CNRS, Université de Bordeaux, 33077 Bordeaux, France; sven.saupe@ibgc.cnrs.fr.
authors.forename: Sven J
authors.initials: SJ
authors.lastname: Saupe
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D048468:Podospora / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; D008164:Luminescent Proteins; D011328:Prions
keywords: amyloid; incompatibility; necroptosis; prion; programmed cell death