Unfolded Protein Response
The unfolded protein response (UPR) is a cellular stress response activated in eukaryotic cells in response to endoplasmic reticulum (ER) stress, an accumulation of unfolded proteins in the ER lumen. ER Stress can be caused by different conditions such as high protein demand, viral infection, energy deprivation or excessive oxidative stress. UPR signalling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate1.
The regulation of UPR is mediated by three major proteins, namely inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK)2. The unfolded Protein Response Regulator BiP/GRP78 has the abiliity to bind and inactivate them3. Misfolded proteins bind and sequester BiP which releases the UPR effector proteins and therefore reactivate them. IRE1α, can also directly bind to misfolded proteins, leading to its activation. Activation of PERK leads to phosphorylation of eukaryotic initiation factor (eIF). Phosphorylated elf-2α inhibits protein translation in order to restore homeostasis and enables ATF4 as well. In response to ER stress, ATF6p90 transits to the Golgi where it is cleaved by MBTPS1 (Membrane-Bound Transcription Factor Peptidase, Site 1) and MBTPS2 (Membrane-Bound Transcription Factor Peptidase, Site 2), yielding the active transcription factor, ATF6p504.
IRE1 oligomerises and activates its ribonuclease domain through auto phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide intron from XBP1u mRNA, in a similar manner to pre-tRNA splicing5. Removal of this intron causes a frame shift in the XBP1 coding sequence resulting in the translation of a 376 amino acid, 40 kDa, XBP-1s isoform.
Active ATF6p50 and XBP1 subsequently bind to the ER stress response element (ERSE) and the UPR element (UPRE), leading to expression of target genes encoding ER chaperones and ER-associated degradation (ERAD) factors involved in degradation of unfolded proteins6. The outcome of UPR activation increases protein folding, transport and ER-associated protein degradation (ERAD), while attenuating protein synthesis to restore ER homeostasis. If these adaptive mechanisms cannot resolve the protein-folding defect, cells enter apoptosis.
The unfolded protein response is essential in regulating immune cell homeostasis, immune surveillance, and neuroinflammation. Chronic ER stress and prolonged UPR activation in microglia and astrocytes contribute to neurodegenerative diseases by modulating cytokine secretion and antigen presentation. This imbalance can either exacerbate neuroinflammation or suppress immune surveillance, leading to pathological protein accumulation. Targeting UPR pathways offers potential therapeutic strategies to restore cellular balance and reduce neurotoxicity in neurodegenerative disorders.8
In cancer, the UPR plays a dual role in T-cell exhaustion and immune evasion. Persistent ER stress can drive immune suppression, while tumor cells exploit UPR pathways to enhance survival and escape immune detection. However, modulating key UPR arms, such as IRE1-XBP1 and PERK-eIF2α, can help reinvigorate anti-tumor immunity. Therapeutic strategies are now focusing on selectively targeting the UPR to reduce immune suppression and enhance T-cell function, making it a promising approach in cancer immunotherapy.
Related Pathways and Resources
References:
- : "The unfolded protein response: controlling cell fate decisions under ER stress and beyond." in: Nature reviews. Molecular cell biology, Vol. 13, Issue 2, pp. 89-102, (2012) (PubMed).
- : "Signal integration in the endoplasmic reticulum unfolded protein response." in: Nature reviews. Molecular cell biology, Vol. 8, Issue 7, pp. 519-29, (2007) (PubMed).
- : "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response." in: Nature cell biology, Vol. 2, Issue 6, pp. 326-32, (2000) (PubMed).
- : "ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs." in: Molecular cell, Vol. 6, Issue 6, pp. 1355-64, (2001) (PubMed).
- : "Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA." in: Molecular cell, Vol. 34, Issue 2, pp. 191-200, (2009) (PubMed).
- : "The unfolded protein response: a stress signaling pathway critical for health and disease." in: Neurology, Vol. 66, Issue 2 Suppl 1, pp. S102-9, (2006) (PubMed).
- : "Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection." in: PLoS pathogens, Vol. 17, Issue 6, pp. e1009644, (2021) (PubMed).
- : "Understanding the Unfolded Protein Response (UPR) Pathway: Insights into Neuropsychiatric Disorders and Therapeutic Potentials." in: Biomolecules & therapeutics, Vol. 32, Issue 2, pp. 183-191, (2024) (PubMed).
- : "The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation." in: Frontiers in aging neuroscience, Vol. 13, pp. 682633, (2021) (PubMed).
