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.ER proteostasis | amyloid L ight-chain amyloidosis (AL) afflicts 8-10 people per million per year, making it the most prominent systemic amyloid disease (1). AL is a gain-of-toxic function disease driven by a clonally expanded plasma cell that secretes amyloidogenic Ig light chains (LCs). These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that interact with distal tissues such as the kidney, heart, and gastrointestinal tract, leading to organ dysfunction and ultimately death by unknown proteotoxicity mechanism(s) (2).The majority of AL patients must combat both a cancer (i.e., the clonally expanded plasma cell) and LC aggregation-associated proteotoxicity. The standard treatment for AL patients is chemotherapy (often combined with stem cell transplant) to eliminate the cancerous plasma cell population (3, 4). The proteasome inhibitor bortezomib, which takes advantage of the stress sensitivity of aggressively proliferating plasma cells, has transformed chemotherapy effectiveness (5-7). Regardless, ∼30% of AL patients with substantial cardiac or renal LC proteotoxicity are too ill at diagnosis to tolerate chemotherapeutics (8-10). Thus, new strategies to reduce LC organ proteotoxicity must be developed to allow more AL patients to take advantage of chemotherapy.LC aggregation requires conformational changes and a sufficient concentration of misfolded LC in plasma, which determine the rate and extent of its concentration-dependent aggregation. Over 500 distinct LC s...

ATF6 Activation Reduces the Secretion and Extracellular Aggregation of Destabilized Variants of an Amyloidogenic Protein

“…For example, stress-free ATF6 activation selectively reduces the secretion and extracellular aggregation of destabilized, amyloidogenic variants of immunoglobulin light chain (LC) (Cooley et al, 2014), indicating that this approach has potential to ameliorate the LC proteotoxicity associated with Light Chain Amyloidosis, a systemic amyloid disease affecting ten people per million per year (Blancas-Mejía and Ramirez-Alvarado, 2013). The capacity for stress-independent ATF6 activation to reduce secretion and subsequent extracellular aggregation of destabilized, amyloidogenic TTR and LC variants, and potentially disease-associated variants of other amyloidogenic proteins (Ryno et al, 2013), bypasses all the challenges associated with establishing protein specific therapies for each systemic amyloid disease, potentially allowing a single therapeutic approach to be broadly applied to these etiologically diverse diseases of protein aggregation.…”

In vivo aspects of protein folding and quality control

“…By contrast, certain neuronal cells are highly sensitive to translational attenuation (175), and the pharmacologic reversal of eIF2a phosphorylation has been shown to improve cognitive memory in mice (176)(177)(178). Numerous small-molecule compounds have been described that activate cellular stress response pathways and reduce the aggregation of disease proteins or enhance their clearance by increasing chaperone levels (13,(179)(180)(181). A key role in aggregation prevention and aggregate dissociation is played by the Hsp70 machinery, as shown by overexpressing single or multiple components of the system in cellular and animal disease models (124,154,182,183).…”

What is new in diagnosis and management of light chain amyloidosis?

“…The possibility of exploiting the intracellular quality control mechanisms to selectively reduce the secretion of misfolded light chains has been recently investigated, with encouraging results. 87 An innovative and very promising approach conceptually derived from the studies on the stabilization of the transthyretin tetramer is aiming at stabilizing the amyloidogenic light chains with small ligands to inhibit their aggregation. Treatment with immune modulatory drugs and decreasing glomerular filtration rate increase the concentration of NT-proBNP, preventing the assessment of cardiac response with this biomarker.…”