Unfolded protein response proteins (UPR proteins) (UPR proteins)

The unfolded protein response (UPR) proteins constitute a vital cellular signaling network that monitors and maintains protein-folding homeostasis within the endoplasmic reticulum (ER) (Hetz et al., 2020). This response is primarily mediated by three ER-resident sensors: inositol-requiring enzyme 1 alpha (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (Walter & Ron, 2011). Under conditions of ER stress, such as the accumulation of misfolded proteins, these sensors are released from the inhibitory chaperone BiP (GRP78) to initiate downstream cascades that expand ER capacity and reduce protein load (Hetz et al., 2019). While the UPR initially serves an adaptive, pro-survival function, chronic or severe stress leads to the activation of terminal UPR signaling, which induces apoptosis through factors like CHOP (DDIT3) (Sano & Reed, 2013). In cancer, the UPR is often constitutively active, allowing tumor cells to survive proteotoxic stress and evade immune detection (Hetz et al., 2013). Conversely, in neurodegenerative and metabolic diseases, the failure of the UPR to resolve stress contributes to progressive cell loss, making these proteins significant targets for small-molecule inhibitors and chemical chaperones (Hetz et al., 2019).

Other names

Endoplasmic reticulum stress proteinsER stress response proteinsUPR signaling componentsER stress transducersEndoplasmic reticulum stress / unfolded protein response proteins

Pharmacological modulation of the unfolded protein response (UPR) involves inhibiting or activating specific signaling arms. IRE1α inhibitors (e.g., KIRA6, 4μ8C) target the kinase or RNase domains to block XBP1 splicing and RIDD activity (Hetz et al., 2019). PERK inhibitors (e.g., GSK2606414) prevent eIF2α phosphorylation, thereby restoring global translation but potentially increasing ER stress (Halliday et al., 2015). ISRIB acts downstream of PERK to activate eIF2B and bypass the inhibitory effects of phospho-eIF2α. Chemical chaperones like 4-phenylbutyric acid (4-PBA) and TUDCA stabilize protein folding to alleviate the underlying ER stress (Cunha et al., 2008).