Chaperoning prions: the cellular machinery for propagating an infectious protein?

Newly made polypeptide chains require the help of molecular chaperones not only to rapidly reach their final three‐dimensional forms, but also to unfold and then correctly refold them back to their biologically active form should they misfold. Most prions are an unusual type of protein that can exist in one of two stable conformations, one of which leads to formation of an infectious alternatively folded form. Studies in Baker's yeast (Saccharomyces cerevisiae) have revealed that prions can exploit the molecular chaperone machinery in the cell in order to ensure stable propagation of the infectious, aggregation‐prone form. The disaggregation of yeast prion aggregates by molecular chaperones generates forms of the prion protein that can seed the protein polymerisation that underlies the prion propagation cycle. In this article, we review what we have learnt about the role of molecular chaperones in yeast prion propagation, describe a model that can explain the role of various classes of molecular chaperones and their co‐chaperones, and speculate on the possible involvement of chaperones in the propagation of mammalian prions. BioEssays 27:823–832, 2005. © 2005 Wiley Periodicals, Inc.

[1]  H. True,et al.  A yeast prion provides a mechanism for genetic variation and phenotypic diversity , 2000, Nature.

[2]  Gary W. Jones,et al.  Amino acid residue 184 of yeast Hsp104 chaperone is critical for prion-curing by guanidine, prion propagation, and thermotolerance , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  O. Donzé,et al.  Hsp104 Interacts with Hsp90 Cochaperones in Respiring Yeast , 2001, Molecular and Cellular Biology.

[4]  B. Szczęśniak,et al.  Ssb1 chaperone is a [PSI +] prion-curing factor , 2001, Current Genetics.

[5]  V. Coustou,et al.  The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Buchner,et al.  Molecular Chaperones — Cellular Machines for Protein Folding , 2002 .

[7]  Bernd Bukau,et al.  The Hsp70 and Hsp60 Chaperone Machines , 1998, Cell.

[8]  A. Horwich,et al.  The Hsp 70 and Hsp 60 Review Chaperone Machines , 1998 .

[9]  F Sherman,et al.  Review: The Cct eukaryotic chaperonin subunits of Saccharomyces cerevisiae and other yeasts , 1996, Yeast.

[10]  C. Ross,et al.  Protein aggregation and neurodegenerative disease , 2004, Nature Medicine.

[11]  Jimena Weibezahn,et al.  Roles of Individual Domains and Conserved Motifs of the AAA+ Chaperone ClpB in Oligomerization, ATP Hydrolysis, and Chaperone Activity* , 2003, The Journal of Biological Chemistry.

[12]  J. Buchner,et al.  Cns1 Is an Activator of the Ssa1 ATPase Activity* , 2004, Journal of Biological Chemistry.

[13]  E. Craig,et al.  Specificity of class II Hsp40 Sis1 in maintenance of yeast prion [RNQ+]. , 2003, Molecular biology of the cell.

[14]  M. Tuite,et al.  Guanidine hydrochloride blocks a critical step in the propagation of the prion-like determinant [PSI(+)] of Saccharomyces cerevisiae. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  F. Hartl,et al.  Chaperonin-mediated de novo generation of prion protein aggregates. , 2001, Journal of molecular biology.

[16]  Y. Chernoff,et al.  Multicopy SUP35 gene induces de-novo appearance of psi-like factors in the yeast Saccharomyces cerevisiae , 1993, Current Genetics.

[17]  M. Mayer,et al.  Hsp70 chaperone machines. , 2001, Advances in protein chemistry.

[18]  Johannes Buchner,et al.  Sti1 Is a Novel Activator of the Ssa Proteins* , 2003, Journal of Biological Chemistry.

[19]  R. Wickner,et al.  [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. , 1994, Science.

[20]  C B Anfinsen,et al.  The formation and stabilization of protein structure. , 1972, The Biochemical journal.

[21]  Changcheng Song,et al.  Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. , 2004, Journal of structural biology.

[22]  Jonathan S Weissman,et al.  Multiple Gln/Asn-Rich Prion Domains Confer Susceptibility to Induction of the Yeast [PSI+] Prion , 2001, Cell.

[23]  A. Fersht,et al.  Is there a unifying mechanism for protein folding? , 2003, Trends in biochemical sciences.

[24]  Y. Chernoff,et al.  Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. , 1996, Genetics.

[25]  L. Pearl,et al.  Structure, function, and mechanism of the Hsp90 molecular chaperone. , 2001, Advances in protein chemistry.

[26]  J. Buchner,et al.  The Prion Curing Agent Guanidinium Chloride Specifically Inhibits ATP Hydrolysis by Hsp104* , 2004, Journal of Biological Chemistry.

[27]  D. Kryndushkin,et al.  Increased Expression of Hsp40 Chaperones, Transcriptional Factors, and Ribosomal Protein Rpp0 Can Cure Yeast Prions* , 2002, The Journal of Biological Chemistry.

[28]  P. Muchowski,et al.  Modulation of neurodegeneration by molecular chaperones , 2005, Nature Reviews Neuroscience.

[29]  D. Kryndushkin,et al.  Yeast [PSI+] Prion Aggregates Are Formed by Small Sup35 Polymers Fragmented by Hsp104* , 2003, Journal of Biological Chemistry.

[30]  Jason C. Young,et al.  Pathways of chaperone-mediated protein folding in the cytosol , 2004, Nature Reviews Molecular Cell Biology.

[31]  D. Masison,et al.  A role for cytosolic hsp70 in yeast [PSI(+)] prion propagation and [PSI(+)] as a cellular stress. , 2000, Genetics.

[32]  S W Liebman,et al.  Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. , 1995, Science.

[33]  Youtao Song,et al.  Propagation of Saccharomyces cerevisiae [PSI+] Prion Is Impaired by Factors That Regulate Hsp70 Substrate Binding , 2004, Molecular and Cellular Biology.

[34]  S. Lindquist,et al.  Hsp104 Catalyzes Formation and Elimination of Self-Replicating Sup35 Prion Conformers , 2004, Science.

[35]  M. Tuite,et al.  Propagation of yeast prions , 2003, Nature Reviews Molecular Cell Biology.

[36]  M. Maddelein,et al.  In vivo aggregation of the HET‐s prion protein of the fungus Podospora anserina , 2001, Molecular microbiology.

[37]  S. Lindquist,et al.  An Arabidopsis heat shock protein complements a thermotolerance defect in yeast. , 1994, The Plant cell.

[38]  M. Tuite,et al.  Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast. , 2003, Genetics.

[39]  Jimena Weibezahn,et al.  Unscrambling an egg: protein disaggregation by AAA+ proteins , 2004, Microbial cell factories.

[40]  Mark S. Boguski,et al.  A repeating amino acid motif in CDC23 defines a family of proteins and a new relationship among genes required for mitosis and RNA synthesis , 1990, Cell.

[41]  R. Wickner,et al.  [URE3] prion propagation is abolished by a mutation of the primary cytosolic Hsp70 of budding yeast , 2004, Yeast.

[42]  J. Tkach,et al.  Amino Acid Substitutions in the C-terminal AAA+ Module of Hsp104 Prevent Substrate Recognition by Disrupting Oligomerization and Cause High Temperature Inactivation* , 2004, Journal of Biological Chemistry.

[43]  S. Lindquist,et al.  Chaperone-supervised conversion of prion protein to its protease-resistant form. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Lindquist,et al.  Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+] , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  L. Müller,et al.  Hsp70 and Hsp90--a relay team for protein folding. , 2004, Reviews of physiology, biochemistry and pharmacology.

[46]  R. Wickner,et al.  Prion Filament Networks in [Ure3] Cells of Saccharomyces cerevisiae , 2001, The Journal of cell biology.

[47]  Arunandan Kumar,et al.  The Chaperone Protein BiP Binds to a Mutant Prion Protein and Mediates Its Degradation by the Proteasome* , 2000, The Journal of Biological Chemistry.

[48]  Y. Chernoff,et al.  Mechanism of Prion Loss after Hsp104 Inactivation in Yeast , 2001, Molecular and Cellular Biology.

[49]  J. Weissman,et al.  The utility of prions. , 2002, Developmental cell.

[50]  R. Wickner,et al.  The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. Brodsky,et al.  HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor , 2002, FEBS letters.

[52]  M. Boguta,et al.  Chaperones that cure yeast artificial [PSI +] and their prion-specific effects , 2000, Current Biology.

[53]  S. Lindquist,et al.  Hsp104, Hsp70, and Hsp40 A Novel Chaperone System that Rescues Previously Aggregated Proteins , 1998, Cell.

[54]  Yoshikazu Nakamura,et al.  [PHI+], a novel Sup35‐prion variant propagated with non‐Gln/Asn oligopeptide repeats in the absence of the chaperone protein Hsp104 , 2003, Genes to cells : devoted to molecular & cellular mechanisms.

[55]  J R Glover,et al.  Support for the Prion Hypothesis for Inheritance of a Phenotypic Trait in Yeast , 1996, Science.

[56]  Y. Chernoff,et al.  Evidence for a Protein Mutator in Yeast: Role of the Hsp70-Related Chaperone Ssb in Formation, Stability, and Toxicity of the [PSI] Prion , 1999, Molecular and Cellular Biology.

[57]  Wah Chiu,et al.  The Structure of ClpB A Molecular Chaperone that Rescues Proteins from an Aggregated State , 2003, Cell.

[58]  S. Lindquist,et al.  Antagonistic Interactions between Yeast Chaperones Hsp104 and Hsp70 in Prion Curing , 1999, Molecular and Cellular Biology.

[59]  S. Lindquist,et al.  The role of Sis1 in the maintenance of the [RNQ+] prion , 2001, The EMBO journal.

[60]  E. Craig,et al.  The Glycine-Phenylalanine-Rich Region Determines the Specificity of the Yeast Hsp40 Sis1 , 1999, Molecular and Cellular Biology.

[61]  R. Wickner,et al.  Prion-Inducing Domain of Yeast Ure2p and Protease Resistance of Ure2p in Prion-Containing Cells , 1995, Science.

[62]  Soojin Lee,et al.  Exchangeable chaperone modules contribute to specification of type I and type II Hsp40 cellular function. , 2003, Molecular biology of the cell.

[63]  M. Tuite,et al.  Guanidine Hydrochloride Inhibits the Generation of Prion “Seeds” but Not Prion Protein Aggregation in Yeast , 2002, Molecular and Cellular Biology.

[64]  D. Masison,et al.  Antagonistic Interactions between Yeast [PSI+] and [URE3] Prions and Curing of [URE3] by Hsp70 Protein Chaperone Ssa1p but Not by Ssa2p , 2002, Molecular and Cellular Biology.

[65]  M. Tuite,et al.  Yeast Prions and Their Prion-Forming Domain , 2000, Cell.

[66]  S. Paushkin,et al.  In vitro propagation of the prion-like state of yeast Sup35 protein. , 1997, Science.

[67]  Luis Moroder,et al.  Structure of TPR Domain–Peptide Complexes Critical Elements in the Assembly of the Hsp70–Hsp90 Multichaperone Machine , 2000, Cell.

[68]  T. Langer,et al.  DnaJ-like proteins: molecular chaperones and specific regulators of Hsp70. , 1994, Trends in biochemical sciences.

[69]  D. Masison,et al.  Saccharomyces cerevisiae Hsp70 mutations affect [PSI+] prion propagation and cell growth differently and implicate Hsp40 and tetratricopeptide repeat cochaperones in impairment of [PSI+]. , 2003, Genetics.

[70]  S. Lindquist,et al.  Strains of [PSI+] are distinguished by their efficiencies of prion‐mediated conformational conversion , 2001, The EMBO journal.

[71]  S. Prusiner.  Novel proteinaceous infectious particles cause scrapie. , 1982, Science.

[72]  E. Craig,et al.  An Essential Role for the Substrate-Binding Region of Hsp40s in Saccharomyces cerevisiae , 2001, The Journal of cell biology.

[73]  R. Wickner,et al.  [URE3] Prion Propagation in Saccharomyces cerevisiae: Requirement for Chaperone Hsp104 and Curing by Overexpressed Chaperone Ydj1p , 2000, Molecular and Cellular Biology.

[74]  Judith Frydman,et al.  Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets. , 2004, Trends in cell biology.

[75]  Susan Lindquist,et al.  Prions as protein-based genetic elements. , 2002, Annual review of microbiology.

[76]  T. Ogura,et al.  Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation. , 2004, Journal of structural biology.

[77]  S. Lindquist,et al.  Rnq1: an epigenetic modifier of protein function in yeast. , 2000, Molecular cell.

[78]  M. Ter‐Avanesyan,et al.  Structure and Replication of Yeast Prions , 1998, Cell.

[79]  B. Roberts,et al.  Prions of yeast as heritable amyloidoses. , 2000, Journal of structural biology.

[80]  L. Neckers,et al.  Modulation of prion protein structural integrity by geldanamycin. , 2003, Glycobiology.

[81]  J. Buchner,et al.  Hsp42 is the general small heat shock protein in the cytosol of Saccharomyces cerevisiae , 2004, The EMBO journal.

[82]  J. Buchner,et al.  Analysis of the Regulation of the Molecular Chaperone Hsp26 by Temperature-induced Dissociation , 2004, Journal of Biological Chemistry.

[83]  B. Bukau,et al.  Size-dependent Disaggregation of Stable Protein Aggregates by the DnaK Chaperone Machinery* , 2000, The Journal of Biological Chemistry.

[84]  J. Brodsky,et al.  Nucleotide Exchange Factor for the Yeast Hsp70 Molecular Chaperone Ssa1p , 2002, Molecular and Cellular Biology.

[85]  S. Liebman,et al.  Prions Affect the Appearance of Other Prions The Story of [PIN+] , 2001, Cell.

[86]  J. Castilla,et al.  The controversial protein-only hypothesis of prion propagation , 2004, Nature Medicine.

[87]  Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family. , 1995, Gene.

[88]  Y. Chernoff,et al.  Huntingtin toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1 , 2002, The Journal of cell biology.

[89]  W. Baumeister,et al.  The proteasome: a supramolecular assembly designed for controlled proteolysis. , 2001, Advances in protein chemistry.

[90]  B. Cox,et al.  Ψ, A cytoplasmic suppressor of super-suppressor in yeast , 1965, Heredity.

[91]  S. Henikoff,et al.  Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity , 2002 .