Ronald Wek
Indiana University School of Medicine
Translational Control and Stress Response Pathways
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.
In addition to global translation repression, eIF2-P 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 reintiation” 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.
Our research is important for understanding the diagnosis, progression, and potential treatment strategies of many different diseases involving disruptions in protein homeostasis and translational control, including diabetes and related metabolic disorders, cancer, and neuropathologies.
References:
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.