E2F deregulation compromises ER homeostasis by attenuating IRE1 activity

The E2F family of transcription factors are key regulators of the cell cycle in all metazoans. While they are primarily known for their role in cell cycle progression, E2Fs also play broader roles in cellular physiology, including the maintenance of exocrine tissue homeostasis. However, the underlying mechanisms that render exocrine cells particularly sensitive to E2F deregulation remain poorly understood. The Drosophila larval salivary gland (SG), like its mammalian counterpart, is an exocrine tissue that produces large quantities of "glue proteins" in the endoplasmic reticulum (ER). Here, we show that E2F activity is important for the exocrine function of the Drosophila SG. The loss of de2f1b, an alternatively spliced isoform of Drosophila E2F1, leads to elevated DNA damage and accumulation of cytoplasmic DNA (cytoDNA) in the SGs. Surprisingly, we found that IRE1, a key sensor of the unfolded protein response, is required not only for ER homeostasis but also for preventing cytoDNA accumulation in the SG. Importantly, we found evidence demonstrating that IRE1 activity is attenuated in de2f1b-deficient SGs, contributing to both ER dysfunction and cytoDNA accumulation. Together, these findings reveal an unanticipated link between ER homeostasis and cytoDNA processing and offer mechanistic insight into why exocrine tissues are particularly vulnerable to E2F deregulation. Author SummaryWe discovered an unexpected consequence of E2F deregulation in ER homeostasis. The loss of de2f1b in the Drosophila salivary gland impedes physiological activation of an ER-resident protein, IRE1, a central component of the unfolded protein response. We show that IRE1 is required not only for ER homeostasis but also for preventing DNA accumulation in the cytoplasm, a phenotype observed in de2f1b deficient salivary glands. Our study reveals a previously uncharacterized role of IRE1-dependent ER function and offers new perspectives on why exocrine tissues are particularly vulnerable to the loss of E2Fs.