Pharmacologic targeting of plasma cell endoplasmic reticulum proteostasis to reduce amyloidogenic light chain secretion

Abstract

Light chain (LC) amyloidosis (AL) involves the toxic aggregation of amyloidogenic immunoglobulin LCs secreted from a clonal expansion of diseased plasma cells. Current AL treatments use chemotherapeutics to ablate the AL plasma cell population. However, no treatments are available that directly reduce the toxic LC aggregation involved in AL pathogenesis. An attractive strategy to reduce toxic LC aggregation in AL involves enhancing endoplasmic reticulum (ER) proteostasis in plasma cells to reduce the secretion and subsequent aggregation of amyloidogenic LCs. Here, we show that the ER proteostasis regulator compound 147 reduces secretion of an amyloidogenic LC as aggregation-prone monomers and dimers in AL patient–derived plasma cells. Compound 147 was established to promote ER proteostasis remodeling by activating the ATF6 unfolded protein response signaling pathway through a mechanism involving covalent modification of ER protein disulfide isomerases (PDIs). However, we show that 147-dependent reductions in amyloidogenic LCs are independent of ATF6 activation. Instead, 147 reduces amyloidogenic LC secretion through the selective, on-target covalent modification of ER proteostasis factors, including PDIs, revealing an alternative mechanism by which this compound can influence ER proteostasis of amyloidogenic proteins. Importantly, compound 147 does not interfere with AL plasma cell toxicity induced by bortezomib, a standard chemotherapeutic used to ablate the underlying diseased plasma cells in AL. This shows that pharmacologic targeting of ER proteostasis through selective covalent modification of ER proteostasis factors is a strategy that can be used in combination with chemotherapeutics to reduce the LC toxicity associated with AL pathogenesis.

Metabolically Activated Proteostasis Regulators Protect Against Glutamate Toxicity by Activating NRF2

“…S4H ). In combination with the existing literature (14, 15, 24, 26, 27), these results suggest that AA147 induces transient ATF6 activity broadly across cell types, whereas AA147-dependent NRF2 activation may only be observed in select cell types including the neuronal-derived HT22 and IMR32 cells.…”

“…Co-treatment with excess AA147 blocked AA147 alk labeling, indicating that these two compounds modify the same proteins in HT22 cells. These results demonstrate that AA147 covalently modifies proteins in HT22 cells, mirroring results observed in other cell types (20, 26).…”

“…These results indicate that AA147 protects against glutamate-induced toxicity in HT22 cells through a mechanism similar to that required for ATF6 activation ( Fig. 2B )(20, 26).…”

“…However, AA147 can also promote protection through ATF6-independent mechanisms. AA147-dependent covalent modification of PDIs, an upstream step involved in AA147-dependent ATF6 activation (20), is sufficient to reduce secretion and toxic aggregation of amyloidogenic immunoglobulin light chains associated with Light Chain Amyloidosis independent of ATF6 signaling (26). Further, AA147 protects the liver against viral infection through an ATF6-independent mechanism (27).…”

Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2

“…AA147-dependent covalent modification of PDIs, an upstream step involved in AA147-dependent ATF6 activation, 20 is sufficient to reduce the secretion and toxic aggregation of amyloidogenic immunoglobulin light chains associated with light chain amyloidosis independent of ATF6 signaling. 27 Further, AA147 protects the liver against viral infection through an ATF6-independent mechanism. 28 These results highlight that apart from ATF6 activation, AA147 can also protect against diverse pathologic insults through mechanisms independent of ATF6 activity.…”