Nucleation seed size determines amyloid clearance and establishes a barrier to prion appearance in yeast

被引:19
作者
Villali, Janice [1 ,5 ]
Dark, Jason [2 ]
Brechtel, Teal M. [3 ]
Pei Fen [3 ,6 ]
Sindi, Suzanne S. [2 ]
Serio, Tricia R. [4 ]
机构
[1] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA
[2] Univ Calif Merced, Dept Appl Math, Merced, CA 95343 USA
[3] Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA
[4] Univ Massachusetts, Dept Biochem & Mol Biol, Amherst, MA 01003 USA
[5] Relay Therapeut, Cambridge, MA USA
[6] BioLegend, San Diego, CA USA
关键词
DE-NOVO APPEARANCE; IN-VIVO; SACCHAROMYCES-CEREVISIAE; PHYSICAL BASIS; PSI+ PRION; SUP35; PROPAGATION; CHAPERONE; HSP104; SPECIFICITY;
D O I
10.1038/s41594-020-0416-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Yeast studies and mathematical modeling reveal a new variable that influences transitions between prion states and persistence of the [PSI+] phenotype: the size of the amyloid seed. Amyloid appearance is a rare event that is promoted in the presence of other aggregated proteins. These aggregates were thought to act by templating the formation of an assembly-competent nucleation seed, but we find an unanticipated role for them in enhancing the persistence of amyloid after it arises. Specifically, Saccharomyces cerevisiae Rnq1 amyloid reduces chaperone-mediated disassembly of Sup35 amyloid, promoting its persistence in yeast. Mathematical modeling and corresponding in vivo experiments link amyloid persistence to the conformationally defined size of the Sup35 nucleation seed and suggest that amyloid is actively cleared by disassembly below this threshold to suppress appearance of the [PSI+] prion in vivo. Remarkably, this framework resolves multiple known inconsistencies in the appearance and curing of yeast prions. Thus, our observations establish the size of the nucleation seed as a previously unappreciated characteristic of prion variants that is key to understanding transitions between prion states.
引用
收藏
页码:540 / +
页数:19
相关论文
共 91 条
[1]   Heterologous Aggregates Promote De Novo Prion Appearance via More than One Mechanism [J].
Arslan, Fatih ;
Hong, Joo Y. ;
Kanneganti, Vydehi ;
Park, Sei-Kyoung ;
Liebman, Susan W. .
PLOS GENETICS, 2015, 11 (01)
[2]   Specificity of prion assembly in vivo -: [PSI+] and [PIN+] form separate structures in yeast [J].
Bagriantsev, S ;
Liebman, SW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (49) :51042-51048
[3]   Prion interference is due to a reduction in strain-specific PrPSc levels [J].
Bartz, Jason C. ;
Kramer, Michelle L. ;
Sheehan, Meghan H. ;
Hutter, Jessica A. L. ;
Ayers, Jacob I. ;
Bessen, Richard A. ;
Kincaid, Anthony E. .
JOURNAL OF VIROLOGY, 2007, 81 (02) :689-697
[4]   Prion variant maintained only at high levels of the Hsp104 disaggregase [J].
Borchsenius, AS ;
Müller, S ;
Newnam, GP ;
Inge-Vechtomov, SG ;
Chernoff, YO .
CURRENT GENETICS, 2006, 49 (01) :21-29
[5]  
Bradley ME, 2003, GENETICS, V165, P1675
[6]   Interactions among prions and prion "strains" in yeast [J].
Bradley, ME ;
Edskes, HK ;
Hong, JY ;
Wickner, RB ;
Liebman, SW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 :16392-16399
[7]   ROLE OF THE CHAPERONE PROTEIN HSP104 IN PROPAGATION OF THE YEAST PRION-LIKE FACTOR [PSI(+)] [J].
CHERNOFF, YO ;
LINDQUIST, SL ;
ONO, B ;
INGEVECHTOMOV, SG ;
LIEBMAN, SW .
SCIENCE, 1995, 268 (5212) :880-884
[8]   A KINETIC-MODEL FOR AMYLOID FORMATION IN THE PRION DISEASES - IMPORTANCE OF SEEDING [J].
COME, JH ;
FRASER, PE ;
LANSBURY, PT .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (13) :5959-5963
[9]   A CYTOPLASMIC SUPPRESSOR OF SUPER-SUPPRESSOR IN YEAST [J].
COX, BS .
HEREDITY, 1965, 20 :505-+
[10]   A Size Threshold Limits Prion Transmission and Establishes Phenotypic Diversity [J].
Derdowski, Aaron ;
Sindi, Suzanne S. ;
Klaips, Courtney L. ;
DiSalvo, Susanne ;
Serio, Tricia R. .
SCIENCE, 2010, 330 (6004) :680-683