title: Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain.
abstract: Light-chain amyloidosis (AL) is a degenerative disease characterized by the extracellular aggregation of a destabilized amyloidogenic Ig light chain (LC) secreted from a clonally expanded plasma cell. Current treatments for AL revolve around ablating the cancer plasma cell population using chemotherapy regimens. Unfortunately, this approach is limited to the ∼ 70% of patients who do not exhibit significant organ proteotoxicity and can tolerate chemotherapy. Thus, identifying new therapeutic strategies to alleviate LC organ proteotoxicity should allow AL patients with significant cardiac and/or renal involvement to subsequently tolerate established chemotherapy treatments. Using a small-molecule screening approach, the unfolded protein response (UPR) was identified as a cellular signaling pathway whose activation selectively attenuates secretion of amyloidogenic LC, while not affecting secretion of a nonamyloidogenic LC. Activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the absence of stress recapitulates the selective decrease in amyloidogenic LC secretion by remodeling the endoplasmic reticulum proteostasis network. Stress-independent activation of XBP1s, or especially ATF6, also attenuates extracellular aggregation of amyloidogenic LC into soluble aggregates. Collectively, our results show that stress-independent activation of these adaptive UPR transcription factors offers a therapeutic strategy to reduce proteotoxicity associated with LC aggregation.
authors.affiliation: Departments of Chemistry, Molecular and Experimental Medicine, and.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Cooley
authors.affiliation: Departments of Chemistry, Molecular and Experimental Medicine, and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ryno
authors.affiliation: Departments of Chemistry, Molecular and Experimental Medicine, and.
authors.forename: Lars
authors.initials: L
authors.lastname: Plate
authors.affiliation: Departments of Chemistry, Molecular and Experimental Medicine, and.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Departments of Chemistry, Molecular and Experimental Medicine, and.
authors.forename: John D
authors.initials: JD
authors.lastname: Hulleman
authors.affiliation: Departments of Chemistry, Molecular and Experimental Medicine, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037 wiseman@scripps.edu jkelly@scripps.edu.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.affiliation: Molecular and Experimental Medicine, and Chemical Physiology, and wiseman@scripps.edu jkelly@scripps.edu.
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005110:Extracellular Space / Q000737:chemistry*; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; D000682:Amyloid; D004268:DNA-Binding Proteins; D007147:Immunoglobulin Light Chains; D066329:Protein Aggregates; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D019284:Thapsigargin; D008156:Luciferases
keywords: ER proteostasis; amyloid