Ronald Wek
Indiana University
School of Medicine
Translational Control and the Stress Response
Pathway
Stress response pathways are the molecular mechanisms by which cells recognize stress conditions and induce translational control that allow for cell adaptation. The Unfolded Protein Response (UPR) is an important example of a regulatory network that responds to disruptions in protein homeostasis in the endoplasmic reticulum (ER). The UPR features sensory proteins, including PERK, which recognize ER stress and induce translational and transcriptional expression networks that serve to expand the processing capacity of the ER and restore cell homeostasis. PERK triggers repression of protein synthesis in response to ER stresses by phosphorylation of the translation initiation factor eIF2 (eIF2-P), limiting the influx of newly synthesized proteins into the ER that can further overload this organelle.
The phosphorylation of eIF2 can occur in response to multiple stress conditions affecting different cell compartments. Hence the translational control driven by eIF2-P is referred to as the Integrated stress response (ISR).
In addition to global translation repression, eIF2-P and the ISR can lead to preferential translation of select mRNAs such as that encoding the transcriptional activator ATF4. We showed that the mechanism of ATF4 preferential translation involves a mechanism of “Delayed translation reinitiation” featuring two short open reading frames (uORFs) in the ATF4 mRNA. Increased translation of ATF4 triggers expression of genes involved in protein folding and assembly and the cellular redox status, which together serve to remedy stress damage.
We also described a “Bypass” mechanism by which eIF2-P enhances the translation of GADD34 (PPP1R15A), a protein phosphatase 1c-targeting subunit, which directs feedback dephosphorylation of eIF2-P. Each of these genes subject to translational control feature distinct uORF configurations, which we view as a form of “bar code” that allows for scanning ribosomes to delineate between mRNAs that are repressed upon phosphorylation of eIF2 from those that are preferentially translated.
References:
Wek RC, Anthony TG, Staschke KA (2023)
Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response Antioxid Redox Signal 39(4-6):351-373
Review
Carlson KR, Georgiadis MM, Tameire F, Staschke KA, Wek RC (2023) Activation of GCN2 by small molecules designed to be inhibitors J Biol Chem 299(4):104595
Amin PH, Carlson KR, Wek RC (2023) An RNA stem-loop function in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response J Biol Chem 299(2):102864
Holmes MJ, Misra J, Wek RC (2022)
Analysis of Translational Control in the Integrated Stress Response by Polysome Profiling
Methods Mol Biol 2022;2428: 157-171
Staschke KA, Wek RC (2019)
Adapting to cell stress from inside and out. Nat Cell Biol 2019 Jul;21(7): 799-800
Review
Wek RC (2018)
Role of eIF2a Kinases in Translational Control and Adaptation to Cellular Stress. Cold Spring Harbor Persepect Biol. Jul 2:10(7)
Review
Young, S.K., and Wek, R.C. (2016)
Upstream open reading frames differentially regulate gene-specific translation in the integrated stress response. Journal of Biological Chemistry 291, 16927-16935.
Young, S.K., Palam, L.R., Wu, C., Sachs, M.S., Wek, R.C. (2016)
Ribosome elongation stall directs gene-specific translation in the Integrated stress response. Journal of Biological Chemistry 291, 6546-6558.
Young, S.K., Willy, J.A., Wu, C., Sachs, M.S., Wek, R.C. (2015)
Ribosome reinitiation directs gene-specific translation and regulates the Integrated stress response. Journal of Biological Chemistry 290, 28257-28271.
Palam, L.R., Baird, T.D., and Wek, R.C. (2011)
Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. Journal of Biological Chemistry 286, 10939-10949.
Dey S., Baird, T.D., Zhou, D., Palam, L.R., Spandau, D.F., Wek, R.C. (2010)
Both transcriptional regulation and translational control of ATF4 are central to the Integrated stress response. Journal of Biological Chemistry 285, 33165-33174.
Vattem, K.M., and Wek, R.C. (2004)
Reinitiation involving upstream open reading frames regulates ATF4 mRNA translation in mammalian cells. Proceedings of National Academy of Science, U.S.A., 101, 11269-11274.