title: ATF6 activation reduces the secretion and extracellular aggregation of destabilized variants of an amyloidogenic protein.
abstract: Systemic amyloidoses result from the aberrant secretion of destabilized, amyloidogenic proteins to the serum where they aggregate into proteotoxic soluble aggregates and amyloid fibrils. Few therapeutic approaches exist to attenuate extracellular pathologic aggregation of amyloidogenic proteins, necessitating the development of new strategies to intervene in these devastating disorders. We show that stress-independent activation of the Unfolded Protein Response-associated transcription factor ATF6 increases ER quality control stringency for the amyloidogenic protein transthyretin (TTR), preferentially reducing secretion of disease-associated TTR variants to an extent corresponding to the variants' destabilization of the TTR tetramer. This decrease in destabilized TTR variant secretion attenuates extracellular, concentration-dependent aggregation of amyloidogenic TTRs into soluble aggregates commonly associated with proteotoxicity in disease. Collectively, our results indicate that increasing ER quality control stringency through ATF6 activation is a strategy to attenuate pathologic aggregation of a destabilized, amyloidogenic protein, revealing a potential approach to intervene in systemic amyloid disease pathology.
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Hulleman
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.affiliation: Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wiseman@scripps.edu.
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D056811:Unfolded Protein Response
chemical_list: D000089982:ADP-Ribosylation Factor 6; D011228:Prealbumin; D011993:Recombinant Fusion Proteins; D013762:Tetrahydrofolate Dehydrogenase; D020727:ADP-Ribosylation Factors