Attribution 4.0 International (CC BY 4.0)2022-11-282022-11-282020-11-05Kasetti, R. B., Patel, P. D., Maddineni, P., Patil, S., Kiehlbauch, C., Millar, J. C., Searby, C. C., Raghunathan, V., Sheffield, V. C., & Zode, G. S. (2020). ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load. Nature communications, 11(1), 5594. https://doi.org/10.1038/s41467-020-19352-12041-1723https://hdl.handle.net/20.500.12503/31990The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.http://creativecommons.org/licenses/by/4.0/Activating Transcription Factor 4 / antagonists & inhibitorsActivating Transcription Factor 4 /geneticsActivating Transcription Factor 4 /metabolismAnimalsAqueous Humor / metabolismCell DeathCells, CulturedEndoplasmic Reticulum Stress / drug effectsEndoplasmic Reticulum Stress / geneticsGlaucoma, Open-Angle / drug therapyGlaucoma, Open-Angle / metabolismGlaucoma, Open-Angle / pathologyHumansMiceOcular Hypertension / drug therapyOcular Hypertension / metabolismOcular Hypertension / pathologyOptic Nerve / metabolismOptic Nerve / pathologyProtein Biosynthesis / drug effectsProtein Phosphatase 1 / geneticsProtein Phosphatase 1 / metabolismRetinal Ganglion Cells / metabolismRetinal Ganglion Cells / pathologySignal TransductionTrabecular Meshwork / drug effectsTrabecular Meshwork / metabolismTrabecular Meshwork / pathologyTranscription Factor CHOP / geneticsTranscription Factor CHOP / metabolismArticle© The Author(s) 2020111