Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain

Christina B. Cooley, Lisa M. Ryno, Lars Plate, Gareth J. Morgan, John D. Hulleman, Jeffery W. Kelly, R. Luke Wiseman

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13046-13051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number36
DOIs
StatePublished - 2014

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Immunoglobulin Light Chains
Unfolded Protein Response
Light
Amyloidosis
Plasma Cells
Drug Therapy
Transcription Factors
Therapeutics
Endoplasmic Reticulum
Kidney

Keywords

  • Amyloid
  • ER proteostasis

ASJC Scopus subject areas

  • General

Cite this

Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. / Cooley, Christina B.; Ryno, Lisa M.; Plate, Lars; Morgan, Gareth J.; Hulleman, John D.; Kelly, Jeffery W.; Wiseman, R. Luke.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 36, 2014, p. 13046-13051.

Research output: Contribution to journalArticle

Cooley, Christina B. ; Ryno, Lisa M. ; Plate, Lars ; Morgan, Gareth J. ; Hulleman, John D. ; Kelly, Jeffery W. ; Wiseman, R. Luke. / Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 36. pp. 13046-13051.
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