Small Molecule ER Proteostasis Regulators Reduce Amyloidogenic Immunoglobulin Light Chain Secretion Through an On-Target, ATF6-Independent Mechanism

The plasma cell secretion and toxic aggregation of amyloidogenic immunoglobulin light chains (LCs) causes proteotoxicity in Light Chain Amyloidosis (AL). We recently identified endoplasmic reticulum (ER) proteostasis regulators such as compound 147 that reduce secretion and aggregation of LCs implicated in AL (Plate, Cooley et al., 2016). Compound 147 promotes adaptive ER proteostasis remodeling through a mechanism involving covalent modification of multiple protein disulfide isomerases (PDIs) and subsequent activation of the ATF6 unfolded protein response (UPR) -associated transcriptional signaling pathway (Paxman, Plate et al., 2018). Here, we show that the 147-dependent reduction in amyloidogenic LC secretion from AL patient plasma cells is independent of ATF6 activation, but instead requires on-target PDI modification. Our results reveal pharmacologic targeting of PDIs as a potential strategy to ameliorate AL-associated proteotoxicity and demonstrate that 147 can influence ER proteostasis through multiple on-target mechanisms including ATF6 activation and PDI modification. IMPACT STATEMENTThis study demonstrates the broad potential for endoplasmic reticulum proteostasis regulator compounds such as 147 to influence secretory proteostasis of disease-associated proteins through multiple on target mechanisms.