PARP7 is a proteotoxic stress sensor that labels proteins for degradation.

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.