title: Adaptation to Stressors by Systemic Protein Amyloidogenesis.
abstract: The amyloid state of protein organization is typically associated with debilitating human neuropathies and is seldom observed in physiology. Here, we uncover a systemic program that leverages the amyloidogenic propensity of proteins to regulate cell adaptation to stressors. On stimulus, cells assemble the amyloid bodies (A-bodies), nuclear foci containing heterogeneous proteins with amyloid-like biophysical properties. A discrete peptidic sequence, termed the amyloid-converting motif (ACM), is capable of targeting proteins to the A-bodies by interacting with ribosomal intergenic noncoding RNA (rIGSRNA). The pathological β-amyloid peptide, involved in Alzheimer's disease, displays ACM-like activity and undergoes stimuli-mediated amyloidogenesis in vivo. Upon signal termination, elements of the heat-shock chaperone pathway disaggregate the A-bodies. Physiological amyloidogenesis enables cells to store large quantities of proteins and enter a dormant state in response to stressors. We suggest that cells have evolved a post-translational pathway that rapidly and reversibly converts native-fold proteins to an amyloid-like solid phase.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Audas
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Audas
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Mathieu D
authors.initials: MD
authors.lastname: Jacob
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: J J David
authors.initials: JJ
authors.lastname: Ho
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Khacho
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Miling
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: J Kishan
authors.initials: JK
authors.lastname: Perera
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Gardiner
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Clay A
authors.initials: CA
authors.lastname: Bennett
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Trajen
authors.initials: T
authors.lastname: Head
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Oleksandr N
authors.initials: ON
authors.lastname: Kryvenko
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Mercé
authors.initials: M
authors.lastname: Jorda
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Daunert
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Trinkle-Mulcahy
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Gonzalgo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Urology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: stephenlee@med.miami.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lee
mesh_terms: D000222:Adaptation, Physiological; D020816:Amino Acid Motifs; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D055592:Biophysical Phenomena; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D018869:Heat-Shock Response; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D012270:Ribosomes / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D022661:RNA, Untranslated
keywords: Hsp70; amyloid-bodies (A-bodies); dormancy; extracellular stress; heat shock chaperones; long noncoding RNA (lncRNA); physiological amyloidogenesis; β-amyloid