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Stress reprograms cells
In a pair of publications, researchers have shown how cells adapt to stressors like water loss by reprogramming their internal signaling networks. The studies describe previously unknown mechanisms that cells use to send signals between cellular machinery and avoid cell death. According to the authors, drugs that enhance these adaptation mechanisms could help cells stave off multiple diseases, including type 2 diabetes. The studies were published in Cell Reports and Molecular Cell.
"We discovered that cells switch off non-essential functions when faced with threats to their survival. At the same time, cells activate new mechanisms to sustain essential functions," says Maria Hatzoglou PhD, senior author on both papers, professor of genetics and nutrition at Case Western Reserve University School of Medicine, and member of the Case Comprehensive Cancer Center.
The studies focus on two types of cellular stress: (1) cell shrinkage from water loss, and (2) dysfunction of the endoplasmic reticulum, that cellular organelle that makes and guides proteins to specific destinations. Both have diverse causes everything from a person's genetics to the cell's environment and cells must adapt to these stressors or perish.
In the new studies, researchers describe a series of cellular workarounds. "Cells protect themselves by slowing down energy-consuming processes, such as protein synthesis. This prepares cells to reprogram the cellular machinery to make only the essential proteins needed for survival," Hatzoglou said. In the Molecular Cell study, Hatzoglou and colleagues describe how stressed cells focus on critical protein production to sustain the function of the endoplasmic reticulum, by transmitting signals along unexpected molecular pathways.
In the Cell Reports study, researchers put cornea cells in salt water to dry them out. The cells responded by activating pathways that help transport amino acids. By doing this, cells were able to prevent water loss a finding which suggests medications targeting transport pathways could help treat dry eye syndrome. Such medications may also help treat neurodegenerative diseases caused by defects in protein equilibrium.
Adds Hatzoglou, "Both our papers contribute to our understandings of the ways cells try to ensure proteins are properly folded and navigated through the cells, so they can reach their final destinations and assume their normal functions. This process is known as the 'integrated stress response.'" In Molecular Cell, researchers outline how cells can "reprogram" an integrated stress response. As the journal explains, the authors "unravel the mechanism of adaptation to chronic stress that encompasses previously unappreciated remodeling."
The Molecular Cell study outlines a cascade of new cellular signals that cells use to adapt to stressful conditions. Interestingly, the novel stress defense described involves remodeling cellular machinery which translates mRNA genetic material into a select group of proteins. This selective protein synthesis protects stressed cells from life-threatening endoplasmic reticulum dysfunction.
In Molecular Cell, Hatzoglou and coworkers also show that endoplasmic reticulum dysfunction is marked by a novel cell death mechanism involving cytoplasmic vacuolization meaning the formation of large, toxic bubbles inside a cell that look like foamy cells themselves observed in many human pathologies. This physical result is a persistent feature in the brains of the neurodegenerative diseases called childhood ataxias, and introduces the interesting possibility that their cause is the result of endoplasmic reticulum dysfunction in nerve cells.
These findings could also lead to new diabetes treatments. "Patients who develop type 2 diabetes become ill because they make too much insulin. This causes the endoplasmic reticulum to be overwhelmed and unable to handle the sudden protein overload, leading to dysfunction. This dysfunction later kills insulin-producing cells in the pancreas," says Hatzoglou. "We believe by enhancing the adaptive response to increase insulin we can delay endoplasmic reticulum dysfunction and the onset of disease." Hatzoglou received funding from the National Institute of Diabetes and Digestive and Kidney Diseases to study how activating cellular stress responses could help delay diabetes progression.
Together with colleagues, Hatzoglou is planning future experiments to understand the molecular mechanisms that defend cells during diverse stress conditions. The findings could lead to new therapeutics to prevent cell death in multiple disease states from dry eye syndrome to diabetes.
Cell Reports GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells
GADD34, a stress-inducible subunit of the PP1 phosphatase, promotes osmoadaptation
The functions of GADD34 in osmoadaptation are independent of its substrate, eIF2?-P
GADD34/PP1 facilitates cis- to trans-Golgi SNAT2 protein trafficking
Pharmacologic and genetic inhibition of GADD34/PP1 induces Golgi fragmentation
GADD34, a stress-induced regulatory subunit of the phosphatase PP1, is known to function in hyperosmotic stress through its well-known role in the integrated stress response (ISR) pathway. Adaptation to hyperosmotic stress is important for the health of corneal epithelial cells exposed to changes in extracellular osmolarity, with maladaptation leading to dry eye syndrome. This adaptation includes induction of SNAT2, an endoplasmic reticulum (ER)-Golgi-processed protein, which helps to reverse the stress-induced loss of cell volume and promote homeostasis through amino acid uptake. Here, we show that GADD34 promotes the processing of proteins synthesized on the ER during hyperosmotic stress independent of its action in the ISR. We show that GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation and is important for cis- to trans-Golgi trafficking of SNAT2, thereby promoting SNAT2 plasma membrane localization and function. These results suggest that GADD34 is a protective molecule for ocular diseases such as dry eye syndrome.
Authors: Dawid Krokowski, Dawid Krokowski, Bo-Jhih Guan, Jing Wu, Yuke Zheng, Padmanabhan P. Pattabiraman, Raul Jobava, Xing-Huang Gao, Xiao-Jing Di, Martin D. Snider, Ting-Wei Mu, Shijie Liu, Brian Storrie, Eric Pearlman, Anna Blumental-Perry, Maria Hatzoglou
This work was supported by the NIH (grants R37-DK60596 and R01-DK53307 to M.H. and grants R01GM092960 and U54GM105814 to B.S.), the VSRC (core grant P30-EY11373 ), and the American Diabetes Association (postdoctoral fellowship 1-17-PDF-129 to X.-H.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH..
Molecular Cell A Unique ISR Program Determines Cellular Responses to Chronic Stress
Protein synthesis during chronic ER stress is independent of eIF2B GEF activity
mRNA translation during chronic ISR is mediated by an eIF3-dependent mechanism
Coordination of transcriptional and translational reprogramming signifies chronic ISR
ER function in chronic ISR relies on PERK-dependent translational reprograming
The integrated stress response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. In acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by normalization of protein synthesis. Here, we report a dramatically different response during chronic ER stress. This chronic ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. The program includes PERK-dependent switching to an eIF3-dependent translation initiation mechanism, resulting in partial, but not complete, translational recovery, which, together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of transcriptional and translational reprogramming prevents ER dysfunction and inhibits foamy cell development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction.
Authors: Bo-Jhih Guan, Vincent van Hoef, Raul Jobava, Orna Elroy-Stein, Leos S. Valasek, Marie Cargnello, Xing-Huang Gao, Dawid Krokowski, William C. Merrick, Scot R. Kimball, Anton A. Komar, Antonis E. Koromilas, Anthony Wynshaw-Boris, Ivan Topisirovi, Ola Larsson, Maria Hatzoglou
The Molecular Cell paper was supported by the Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the National Genomics Infrastructure funded by the Swedish Research Council, and the Uppsala Multidisciplinary Center for Advanced Computational Science. The latter organization provided assistance with massive parallel sequencing efforts and access to the UPPMAX computational infrastructure. This work was also supported by grants from the National Institutes of Health (DK060596 and DK053307 to MH; DK013499 to SRK), the Canadian Cancer Society Research Institute (#703816 to IT), Canadian Institutes of Health Research (#PJT-148603 to IT and MOP-13713 to AEK), STINT (#2012-2073 to OL and IT), the Wallenberg Academy Fellow program (to OL), the Swedish Research Council (to OL), the Swedish Cancer Society (to OL), the Czech Science Foundation (GA17-06238S to L.S.V.), the Wellcome Trust (090812/B/09/Z to LSV), and the American Diabetes Association (1-17-PDF-129 to X-HG). IT is a Junior 2 Research Scholar of the Fonds de Recherche du Que ?bec - Sante ? (FRQ-S).
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Research has identified that integrated stress response (ISR) is induced by
endoplasmic reticulum (ER) stress that results in its dysfunction.