Endoplasmic reticulum stress and the unfolded protein response: emerging regulators in progression of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a common trauma with high mortality and disability rates worldwide. However, the current management of this disease is still unsatisfactory. Therefore, it is necessary to investigate the pathophysiological mechanisms of TBI in depth to improve the treatment options. In recent decades, abundant evidence has highlighted the significance of endoplasmic reticulum stress (ERS) in advancing central nervous system (CNS) disorders, including TBI. ERS following TBI leads to the accumulation of unfolded proteins, initiating the unfolded protein response (UPR). Protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6) are the three major pathways of UPR initiation that determine whether a cell survives or dies. This review focuses on the dual effects of ERS on TBI and discusses the underlying mechanisms. It is suggested that ERS may crosstalk with a series of molecular cascade responses, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, autophagy, and cell death, and is thus involved in the progression of secondary injury after TBI. Hence, ERS is a promising candidate for the management of TBI.

Fig. 1. Schematic diagram of the ERS and UPR pathways.

Created with BioRender.com. ER endoplasmic reticulum, UPR unfolded protein response, PERK protein kinase RNA-like ER kinase, eIF2α eukaryotic translation initiation factor 2 alpha, p-eIF2α: phosphorylated eIF2α, ATF4 activating transcription factor 4, PP1 type 1 protein phosphatase, GADD34 growth arrest and DNA damage-inducible gene 34, IRE1 inositol-requiring protein 1, XBP-1 X box binding protein 1, XBP-1s spliced XBP-1, RIDD regulated IRE1α‑dependent decay, ATF6 activating transcription factor 6, ATF6f fragment of ATF6α, ERAD ER-associated degradation, GLS Golgi-localization signal, S1P site-1 protease, S2P site-2 protease.

Fig. 2. A schematic representation of ERS and mitochondrial dysfunction as well as oxidative stress.

Created with BioRender.com. PERK protein kinase RNA-like ER kinase, Mfn2 mitofusin 2, Nrf2 nuclear factor erythroid 2-related factor 2, Keap1 Kelch-like ECH-associated protein 1, IRE1 inositol-requiring protein 1, Sig-1R sigma-1 receptor, IP₃R inositol trisphosphate receptor, Grp75 75 kDa glucose-regulated protein, VDAC voltage-dependent anion channel, MCU mitochondrial calcium uniporter, ATF6 activating transcription factor 6, VABP recombinant vesicle-associated membrane protein-associated protein B, CHOP C/EBP-homologous protein, Ero1α ER oxidase 1 alpha, ROS reactive oxygen species, PRDX4 peroxiredoxin 4, GPX7 glutathione peroxidase 7, GPX8 glutathione peroxidase 8, mPTP mitochondrial permeability transition pore.

Fig. 3. Schematic diagram of ERS-induced apoptosis.

Created with BioRender.com. Bcl-xl B-cell lymphoma-extra large, Bcl-2 B-cell lymphoma 2, Bak Bcl-2 homologous antagonist-killer protein, Bax Bcl-2-associated X protein, Bim Bcl-2 interacting mediator of cell death, Mcl-1 myeloid cell leukemia sequence 1 protein, TNF tumor necrosis factor, TRAIL TNF-related apoptosis-inducing ligand, TNFR1 tumor necrosis factor receptor 1, TRAF2 tumor necrosis factor receptor-associated factor 2, DR death receptor, FADD Fas-associated death domain, IRE1 inositol-requiring protein 1, ASK1 apoptosis signal-regulating kinase 1, JNK c-Jun N-terminal kinase, PERK protein kinase RNA-like ER kinase, eIF2α eukaryotic translation initiation factor 2 alpha, ATF activating transcription factor, CHOP C/EBP-homologous protein, IP₃R inositol trisphosphate receptor, RYR ryanodine receptor, mPTP mitochondrial permeability transition pore, CytC cytochrome c.

Fig. 4. The intricate association between ERS and various pathologies after TBI.

Created with BioRender.com. PERK protein kinase RNA-like ER kinase, CREB cyclic adenosine monophosphate response element binding protein, PSD95 postsynaptic density 95, Sig-1R Sigma-1 receptor, P66Shc the 66 Kd Shc protein, Nrf2 nuclear factor erythroid 2-related factor 2, PRDX4 peroxiredoxin 4, GPX7/8 glutathione peroxidase 7/8, eIF2α eukaryotic translation initiation factor 2 alpha, ATF4/6 activating transcription factor4/6, CHOP C/EBP-homologous protein, ASK1 apoptosis signal-regulating kinase 1, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, NF-κB nuclear factor-kappa B, I-IFN type I interferon, STING stimulator of interferon genes, XBP-1 X-box binding protein.