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.

中文翻译：

---

ER蛋白质稳态调节剂通过靶向ATF6的独立机制减少淀粉样蛋白轻链分泌

淀粉样蛋白生成的免疫球蛋白轻链（LCs）的浆细胞分泌和毒性聚集导致轻链淀粉样变性病（AL）发生蛋白毒性。我们最近发现了内质网（ER）蛋白质稳定调节剂，例如化合物147，可减少与AL有关的LC的分泌和聚集（Plate，Cooley等，2016）。化合物147通过涉及多种蛋白二硫键异构酶（PDI）的共价修饰和随后ATF6未折叠蛋白应答（UPR）相关的转录信号通路的激活的机制促进ER蛋白重建的适应性（Paxman，Plate et al。，2018）。在这里，我们显示从AL患者浆细胞中淀粉样蛋白产生的LC分泌的147依赖性减少与ATF6激活无关，而是需要按目标PDI修饰。