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Unfolded Protein Response Activation Reduces Secretion and Extracellular Aggregation of Amyloidogenic Immunoglobulin Light Chain
Proceedings of the National Academy of Sciences of the United States of America (2014)
  • Christina B Cooley, The Scripps Research Institute
  • Lisa M Ryno
  • Lars Plate
  • Gareth J Morgan
  • John D Hulleman
  • Jeffrey W Kelly
  • R Luke Wiseman

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.

  • ER proteostasis,
  • amyloid
Publication Date
September, 2014
Citation Information
Cooley, C. B., Ryno, L. M., Plate, L., Morgan, G. J., Hulleman, J. D., Kelly, J. W., & Wiseman, R. L. (2014). Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. Proceedings of the National Academy of Sciences of the United States of America, 111, 13046-13051. doi: 10.1073/pnas.1406050111