Expanding the landscape of the unfolded protein response: The roles of secondary transcription factors in development and disease

The unfolded protein response (UPR) of the endoplasmic reticulum (ER) is a classic cellular reaction to stress that helps restore ER homeostasis. However, growing evidence demonstrates that the main UPR effectors (Activating Transcription Factor 6 (ATF6), X-box Binding Protein 1 (XBP1s), and Activating Transcription Factor 4 (ATF4)) not only regulate canonical UPR target genes but also promote the transcription of genes encoding secondary transcription factors (TFs). These secondary TFs contribute to ER homeostasis maintenance and are involved in various physiological processes that extend beyond the traditional UPR. In this review, we examine the secondary TFs activated by UPR master regulators (UPR-TFs) and discuss their functional roles in different tissues and organs. We emphasize how these secondary TFs, controlled by their respective UPR-TFs, participate in stress responses, cell differentiation, embryonic development, circadian rhythms, metabolism, and other physiological processes. Furthermore, we explore common signaling pathways and tissue- and cell-specific regulatory mechanisms, highlighting convergence points where secondary TFs from different UPR branches intersect, indicating a more complex regulatory network. We also discuss the functions of these secondary TFs in the lungs, placenta, testis, uterus, pancreas, and liver, as well as during embryonic development and in pathological conditions. This study reveals biological activities that extend beyond the traditional roles of the UPR, providing a broader view of this signaling pathway and opening new avenues for future research.