ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

dc.creatorKasetti, Ramesh B.
dc.creatorPatel, Pinkal D.
dc.creatorMaddineni, Prabhavathi
dc.creatorPatil, Shruti
dc.creatorKiehlbauch, Charles
dc.creatorMillar, J. Cameron
dc.creatorSearby, Charles C.
dc.creatorRaghunathan, Vijaykrishna
dc.creatorSheffield, Val C.
dc.creatorZode, Gulab S.
dc.creator.orcid0000-0002-7823-2595 (Zode, Gulab S.)
dc.description.abstractThe 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.
dc.identifier.citationKasetti, 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.
dc.publisherSpringer Nature
dc.rights.holder© The Author(s) 2020
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.sourceNature Communications
dc.subject.meshActivating Transcription Factor 4 / antagonists & inhibitors
dc.subject.meshActivating Transcription Factor 4 /genetics
dc.subject.meshActivating Transcription Factor 4 /metabolism
dc.subject.meshAqueous Humor / metabolism
dc.subject.meshCell Death
dc.subject.meshCells, Cultured
dc.subject.meshEndoplasmic Reticulum Stress / drug effects
dc.subject.meshEndoplasmic Reticulum Stress / genetics
dc.subject.meshGlaucoma, Open-Angle / drug therapy
dc.subject.meshGlaucoma, Open-Angle / metabolism
dc.subject.meshGlaucoma, Open-Angle / pathology
dc.subject.meshOcular Hypertension / drug therapy
dc.subject.meshOcular Hypertension / metabolism
dc.subject.meshOcular Hypertension / pathology
dc.subject.meshOptic Nerve / metabolism
dc.subject.meshOptic Nerve / pathology
dc.subject.meshProtein Biosynthesis / drug effects
dc.subject.meshProtein Phosphatase 1 / genetics
dc.subject.meshProtein Phosphatase 1 / metabolism
dc.subject.meshRetinal Ganglion Cells / metabolism
dc.subject.meshRetinal Ganglion Cells / pathology
dc.subject.meshSignal Transduction
dc.subject.meshTrabecular Meshwork / drug effects
dc.subject.meshTrabecular Meshwork / metabolism
dc.subject.meshTrabecular Meshwork / pathology
dc.subject.meshTranscription Factor CHOP / genetics
dc.subject.meshTranscription Factor CHOP / metabolism
dc.titleATF4 leads to glaucoma by promoting protein synthesis and ER client protein load


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