ALLC-GLuc reporter screening identifies UPR modulators able to reduce secretion of amyloidogenic LC. (A) Schematic of GLuc, ALLC-GLuc, and ERSE-FLuc reporter constructs used in stable ARPE19 or HEK293T-Rex cell lines. ERSE-FLuc transcriptional reporter includes the ERSE-containing portion of the BiP promoter upstream of the firefly luciferase (FLuc) gene. SS, signal sequence. (B) Plot of LOPAC screening data comparing ALLC-GLuc secretion vs. GLuc secretion. ARPE-19 cells stably expressing ALLC-GLuc or GLuc alone were treated with compound (10 μM) for 24 h. Shaded blue section indicates compounds that reduce ALLC-GLuc secretion (>25%) and do not affect GLuc secretion (<±15% from DMSO control). (C) Plot of LOPAC screening results comparing ALLC-GLuc secretion (ARPE-19 cells, 24-h treatment) vs. UPR activation (ERSE-FLuc expressing HEK293T-Rex cells, 18-h treatment). Compounds falling below the horizontal line reduce ALLC-GLuc secretion by 25%. Compounds falling to the right of the vertical line increase ERSE-FLuc expression >1.5-fold relative to DMSO control. Compounds depicted in red are known activators of the UPR.