Although our Mesoscale ELISA method shows significant advantages over commonly used, VEID-based assay systems to measure caspase-6 activity, it still requires manual cell lysis and protein quantification steps that are not easily amenable to highthroughput screening campaigns. We therefore turned to a highcontent imaging platform that allows automated liquid handling as well as immunofluorescence imaging and quantification. Using a primary antibody specific for caspase-6 cleaved lamin A, we found increased perinuclear staining in C6wt cells after induction of cell death by camptothecin (Fig. 6A) . The observed blebbing of the nuclear membrane is consistent with the breakdown of the nuclear lamina during apoptosis. No staining for cleaved lamin protein was observed in non-stressed C6wt, non-stressed C6ko or camptothecin-stressed C6ko cells (Fig. 6A ). Using nuclear DAPI staining as a reference point, we quantified the perinuclear immunofluorescence in a ring around the nucleus (Fig. 6A, insets) , and found a 2fold increase in staining intensity in camptothecin-stressed versus non-stressed wt MEFs (Fig. 6B) . Only background signal was observed in C6ko MEFs even after camptothecin treatment, indicating that the detection of cleaved lamin A by immunofluorescence is also specific to caspase-6 (Fig. 6B) . This method is ideally suited for the high-throughput intracellular testing of modulators of caspase-6 activity in in the presence of confounding proteolytic activity, i.e. that of caspase-3.