Ikenga Nonso J, Vervoorts Jörg, Lüscher Bernhard, Žaja Roko, Feijs-Žaja Karla L H
Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
EMBO J. 2025 Aug 20. doi: 10.1038/s44318-025-00545-7.
ADP-ribosylation is a post-translational modification that plays a critical role in cellular stress responses. We have observed that during proteotoxic stress, cellular ADP-ribosylation increases, with ADP-ribosylated proteins accumulating in cytoplasmic foci containing ubiquitin and p62. During prolonged stress, these ADP-ribosylated proteins are transported to aggresomes and subsequently degraded via autophagy. In the absence of ubiquitination, ADP-ribosylated proteins become more prevalent and less soluble, indicating that ubiquitination is indispensable for this process. Upon inhibition of PARP7, accumulation of mono(ADP-ribosyl)ated proteins in response to proteotoxic stress is impeded. PARP7 turnover is very high under normal conditions; however, the protein becomes stabilised following proteotoxic stress and thereby forms an ideal proteotoxic stress sensor. Our findings imply that, contrary to the current paradigm, not all ADP-ribosylation may occur on specific sites to regulate specific protein characteristics. Instead, it may be rather promiscuous to enable efficient protein degradation or segregation to prevent irreversible damage caused by defective proteins.
ADP核糖基化是一种翻译后修饰，在细胞应激反应中起关键作用。我们观察到，在蛋白毒性应激期间，细胞内的ADP核糖基化增加，ADP核糖基化蛋白积聚在含有泛素和p62的细胞质病灶中。在长时间应激期间，这些ADP核糖基化蛋白被转运至聚集体，随后通过自噬降解。在缺乏泛素化的情况下，ADP核糖基化蛋白变得更为普遍且溶解性降低，这表明泛素化对于此过程不可或缺。抑制PARP7后，蛋白毒性应激反应中单次（ADP-核糖基）化蛋白的积累受到阻碍。PARP7在正常条件下的周转非常快；然而，在蛋白毒性应激后该蛋白会变得稳定，从而形成一种理想的蛋白毒性应激传感器。我们的研究结果表明，与当前的范式相反，并非所有的ADP核糖基化都可能发生在特定位点以调节特定蛋白质特性。相反，它可能相当随意，以实现蛋白质的有效降解或隔离，防止有缺陷的蛋白质造成不可逆转的损害。
