Xeroderma pigmentosum protein XPD controls caspase-mediated stress responses

• Published in: Nature communications 2024-10, Vol.15 (1), p.9344-13, Article 9344
• Main Authors: Wei, Hai, Weaver, Yi M., Weaver, Benjamin P.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/2; 13/89; 14; 14/35; 38; 38/77; 42; 631/337/1427/2566; 631/80/82; 631/80/86/2366; 64; 64/11; 82/58; Animals; Apoptosis; Apoptosis - radiation effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Caspase; Caspases - genetics; Caspases - metabolism; Cell death; Cellular stress response; DNA Damage; Genotoxicity; Humanities and Social Sciences; Humans; Irradiation; multidisciplinary; Osmotic Pressure; Proteins; Proteolysis; Science; Science (multidisciplinary); Stress, Physiological; Ultraviolet radiation; Ultraviolet Rays; Xeroderma pigmentosum; Xeroderma Pigmentosum - genetics; Xeroderma Pigmentosum - metabolism; Xeroderma Pigmentosum Group D Protein - genetics; Xeroderma Pigmentosum Group D Protein - metabolism; XPD protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53755-8

Caspases regulate and execute a spectrum of functions including cell deaths, non-apoptotic developmental functions, and stress responses. Despite these disparate roles, the same core cell-death machinery is required to enzymatically activate caspase proteolytic activities. Thus, it remains enigmatic how distinct caspase functions are differentially regulated. In this study, we show that Xeroderma pigmentosum protein XPD has a conserved function in activating the expression of stress-responsive caspases in C. elegans and human cells without triggering cell death. Using C. elegans , we show XPD-1-dependent activation of CED-3 caspase promotes survival upon genotoxic UV irradiation and inversely suppresses responses to non-genotoxic insults such as ER and osmotic stressors. Unlike the TFDP ortholog DPL-1 which is required for developmental apoptosis in C. elegans , XPD-1 only activates stress-responsive functions of caspase. This tradeoff balancing responses to genotoxic and non-genotoxic stress may explain the seemingly contradictory nature of caspase-mediated stress resilience versus sensitivity under different stressors. How caspases are differentially regulated in non-apoptotic stress responses remains enigmatic. Here, the authors show that Xeroderma pigmentosum protein XPD promotes stress specific caspase expression to balance genotoxic and non-genotoxic responses.