bims-ershed 2021-11-21 papers

Pancreatology. 2021 Oct 28. pii: S1424-3903(21)00610-4. [Epub ahead of print]

The unfolded protein response: An emerging therapeutic target for pancreatitis and pancreatic ductal adenocarcinoma.

M Teresa Borrello, Mickenzie B Martin, Christopher L Pin.

Pancreatitis is a debilitating disease involving inflammation and fibrosis of the exocrine pancreas. Recurrent or chronic forms of pancreatitis are a significant risk factor for pancreatic ductal adenocarcinoma. While genetic factors have been identified for both pathologies, environmental stresses play a large role in their etiology. All cells have adapted mechanisms to handle acute environmental stress that alters energy demands. A common pathway involved in the stress response involves endoplasmic reticulum stress and the unfolded protein response (UPR). While rapidly activated by many external stressors, in the pancreas the UPR plays a fundamental biological role, likely due to the high protein demands in acinar cells. Despite this, increased UPR activity is observed in response to acute injury or following exposure to risk factors associated with pancreatitis and pancreatic cancer. Studies in animal and cell cultures models show the importance of affecting the UPR in the context of both diseases, and inhibitors have been developed for several specific mediators of the UPR. Given the importance of the UPR to normal acinar cell function, efforts to affect the UPR in the context of disease must be able to specifically target pathology vs. physiology. In this review, we highlight the importance of the UPR to normal and pathological conditions of the exocrine pancreas. We discuss recent studies suggesting the UPR may be involved in the initiation and progression of pancreatitis and PDAC, as well as contributing to chemoresistance that occurs in pancreatic cancer. Finally, we discuss the potential of targeting the UPR for treatment.

Keywords: (ATF6); (IRE1); (PDAC); (PERK); Activating transcription factor 6; ER stress Response; Inositol requiring enzyme 1; Integrated stress response; Pancreatic ductal adenocarcinoma; Pancreatitis; Protein kinase RNA-like ER kinase

DOI: https://doi.org/10.1016/j.pan.2021.10.007

Neuron. 2021 Nov 09. pii: S0896-6273(21)00862-X. [Epub ahead of print]

Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking.

Iva Stojkovska, Willayat Y Wani, Friederike Zunke, Nandkishore R Belur, Egor A Pavlenko, Nkatha Mwenda, Karan Sharma, Laetitia Francelle, Joseph R Mazzulli.

Neurodegenerative disorders are characterized by a collapse in proteostasis, as shown by the accumulation of insoluble protein aggregates in the brain. Proteostasis involves a balance of protein synthesis, folding, trafficking, and degradation, but how aggregates perturb these pathways is unknown. Using Parkinson's disease (PD) patient midbrain cultures, we find that aggregated α-synuclein induces endoplasmic reticulum (ER) fragmentation and compromises ER protein folding capacity, leading to misfolding and aggregation of immature lysosomal β-glucocerebrosidase. Despite this, PD neurons fail to initiate the unfolded protein response, indicating perturbations in sensing or transducing protein misfolding signals in the ER. Small molecule enhancement of ER proteostasis machinery promotes β-glucocerebrosidase solubility, while simultaneous enhancement of trafficking improves ER morphology, lysosomal function, and reduces α-synuclein. Our studies suggest that aggregated α-synuclein perturbs the ability of neurons to respond to misfolded proteins in the ER, and that synergistic enhancement of multiple proteostasis branches may provide therapeutic benefit in PD.

Keywords: ER stress; Parkinson's disease; alpha-synuclein; beta-glucocerebrosidase; iPSC-derived midbrain dopaminergic neurons; lysosomal dysfunction; protein aggregation

DOI: https://doi.org/10.1016/j.neuron.2021.10.032

ACS Chem Biol. 2021 Nov 19.

Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2.

Jessica D Rosarda, Kelsey R Baron, Kayla Nutsch, Gabriel M Kline, Caroline Stanton, Jeffery W Kelly, Michael J Bollong, R Luke Wiseman.

The extracellular accumulation of glutamate is a pathologic hallmark of numerous neurodegenerative diseases including ischemic stroke and Alzheimer's disease. At high extracellular concentrations, glutamate causes neuronal damage by promoting oxidative stress, which can lead to cellular death. This has led to significant interest in developing pharmacologic approaches to mitigate the oxidative toxicity caused by high levels of glutamate. Here, we show that the small molecule proteostasis regulator AA147 protects against glutamate-induced cell death in a neuronal-derived cell culture model. While originally developed as an activator of the activating transcription factor 6 (ATF6) arm of the unfolded protein response, this AA147-dependent protection against glutamate toxicity is primarily mediated through activation of the NRF2-regulated oxidative stress response. We demonstrate that AA147 activates NRF2 selectively in neuronal-derived cells through a mechanism involving metabolic activation to a reactive electrophile and covalent modification of KEAP1─a mechanism analogous to that involved in the AA147-dependent activation of ATF6. These results define the potential for AA147 to protect against glutamate-induced oxidative toxicity and highlight the potential for metabolically activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 stress-responsive signaling pathways to mitigate oxidative damage associated with diverse neurologic diseases.

DOI: https://doi.org/10.1021/acschembio.1c00810

Biomed Res Int. 2021 ;2021 8717565

Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model.

Mei-Ying Huang, Dian-Wei Wan, Jie Deng, Wen-Jie Guo, Yue Huang, Huan Chen, De-Lin Xu, Zhi-Gang Jiang, Yuan Xue, Yi-Huai He.

Background: Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model.
Methods: In vivo and in vitro experiments were carried out. LO2 cells were treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with carbon tetrachloride (CCl4, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined.
Results: TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression (p < 0.05) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress (p < 0.05). Similar results were observed in CCl4 or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl4-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers (p < 0.05). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress.
Conclusions: Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.

DOI: https://doi.org/10.1155/2021/8717565

Cell Biochem Biophys. 2021 Nov 20.

Heme Oxygenase 1 in Vertebrates: Friend and Foe.

Rafael Cardoso Maciel Costa Silva, Leonardo Holanda Travassos Correa.

HO-1 is the inducible form of the enzyme heme-oxygenase. HO-1 catalyzes heme breakdown, reducing the levels of this important oxidant molecule and generating antioxidant, anti-inflammatory, and anti-apoptotic byproducts. Thus, HO-1 has been described as an important stress response mechanism during both physiologic and pathological processes. Interestingly, some findings are demonstrating that uncontrolled levels of HO-1 byproducts can be associated with cell death and tissue destruction as well. Furthermore, HO-1 can be located in the nucleus, influencing gene transcription, cellular proliferation, and DNA repair. Here, we will discuss several studies that approach HO-1 effects as a protective or detrimental mechanism in different pathological conditions. In this sense, as the major organs of vertebrates will deal specifically with distinct types of stresses, we discuss the HO-1 role in each of them, exposing the contradictions associated with HO-1 expression after different insults and circumstances.

Keywords: Brain; Gastrointestinal system; Heme-oxygenase; Kidneys; Liver; Lungs; Reproductive tract; Skin; Stress response

DOI: https://doi.org/10.1007/s12013-021-01047-z