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

Cooley CB, Ryno LM, Plate L, Morgan GJ, Hulleman JD, Kelly JW, Wiseman RL
Proc Natl Acad Sci U S A. 2014 111 (36): 13046-51

PMID: 25157167 · PMCID: PMC4246986 · DOI:10.1073/pnas.1406050111

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.

MeSH Terms (18)

Activating Transcription Factor 6 Amyloid DNA-Binding Proteins Extracellular Space Genes, Reporter HEK293 Cells Humans Immunoglobulin Light Chains Luciferases Protein Aggregates Protein Stability Proteolysis Regulatory Factor X Transcription Factors Stress, Physiological Thapsigargin Transcription Factors Unfolded Protein Response X-Box Binding Protein 1

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