Mitochondrial signalling plays a fundamental role in orchestrating essential intracellular functions, including cellular respiration, proliferation, nucleic acid synthesis, and oxidative stress management. The activation of calpain, a group of Ca2+-dependent cysteine proteases, by ROS-induced oxidative stress is linked to cancer progression. Calpain can be activated by ROS either through intracellular Ca2+ elevation or via oxidative modifications of the protease, altering protein susceptibility to calpain cleavage. In tumour cell biology, ROS-activated calpains influence cell survival, migration, proliferation, apoptosis, and invasiveness. Several studies report unusual calpain expression in cancer cells. Various anticancer drugs induce cytotoxicity by activating calpain, significantly impacting cancer treatment strategies. This unique review explores the perspective of ROS-induced calpain activation and its pivotal role in cancer progression and therapeutics

PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways. © The Author(s) 2024.; (Figure presented.) Mono-ADP-ribosylation has emerged as a crucial factor in innate immune responses, but is understudied due to the lack of sensitive detection methods. This study visualizes endogenous interferon-induced ADP-ribosylation and shows that PARP14 is a major enzyme responsible for this signalling event. Immunity responses induce PARP14-dependent ADP-ribosylation. SARS2-CoV2 Mac1 can remove PARP14-dependent ADP-ribosylation. PARP14, PARP9 and DTX3L regulate the formation of ubiquitin and ADPr foci in the cytoplasm. PARP14 activity is regulated by PARP9/DTX3L, through (1) the hydrolytic activity of PARP9 and (2) PARP14 interaction with DTX3L. © The Author(s) 2024.

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