Abstract
BACKGROUND: The cellular proteostasis machinery is essential for maintaining protein homeostasis by employing quality control systems that identify, sequester, and eliminate damaged or misfolded proteins. However, the accumulation of misfolded proteins can overwhelm these protective mechanisms, disrupting proteostasis. This phenomenon is a hallmark of numerous pathologies, including a variety of genetic disorders. In the secretory pathway, the buildup of misfolded proteins triggers endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). The UPR serves as an adaptive mechanism, aiming to alleviate stress and restore cellular homeostasis. However, if ER stress is prolonged or severe, the UPR may fail to restore balance and apoptosis is induced. SUMMARY: This review introduces the intricate signaling pathways activated by the three UPR transmembrane sensors: protein-kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We briefly present the roles of the distinct transcriptional programs activated by each sensor in modulating the cellular response to protein stress and in determining cell fate. We discuss how genetic variants and environmental factors contribute to the heterogeneity observed in protein misfolding diseases. Finally, we critically evaluate select therapeutic strategies, specifically protein stabilization, trafficking modulation, and UPR sensor targeting approaches. KEY MESSAGES: This review introduces the potential consequences of protein misfolding, which may not only impair protein function but can also lead to toxic protein accumulation and stress induction. Using Fabry disease as a compelling example, we suggest that future therapeutic intervention may require nuanced, combination approaches that address both loss and gain of protein function.