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

Ramesh B Kasetti; Pinkal D Patel; Prabhavathi Maddineni; Shruti Patil; Charles Kiehlbauch; J Cameron Millar; Charles C Searby; VijayKrishna Raghunathan; Val C Sheffield; Gulab S Zode

doi:10.1038/s41467-020-19352-1

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

Journal article

Open access

Peer reviewed

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

Ramesh B Kasetti, Pinkal D Patel, Prabhavathi Maddineni, Shruti Patil, Charles Kiehlbauch, J Cameron Millar, Charles C Searby, VijayKrishna Raghunathan, Val C Sheffield and Gulab S Zode

Nature communications, Vol.11(1), pp.5594-5594

11/05/2020

DOI: 10.1038/s41467-020-19352-1

PMCID: PMC7644693

PMID: 33154371

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Abstract

The 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.

Optic Nerve - pathology

Transcription Factor CHOP - genetics

Humans

Trabecular Meshwork - drug effects

Glaucoma, Open-Angle - pathology

Ocular Hypertension - metabolism

Endoplasmic Reticulum Stress - genetics

Retinal Ganglion Cells - metabolism

Ocular Hypertension - drug therapy

Retinal Ganglion Cells - pathology

Aqueous Humor - metabolism

Cell Death

Protein Phosphatase 1 - genetics

Glaucoma, Open-Angle - metabolism

Trabecular Meshwork - pathology

Activating Transcription Factor 4 - antagonists & inhibitors

Endoplasmic Reticulum Stress - drug effects

Signal Transduction

Ocular Hypertension - pathology

Cells, Cultured

Activating Transcription Factor 4 - genetics

Glaucoma, Open-Angle - drug therapy

Protein Phosphatase 1 - metabolism

Animals

Activating Transcription Factor 4 - metabolism

Trabecular Meshwork - metabolism

Protein Biosynthesis - drug effects

Mice

Transcription Factor CHOP - metabolism

Optic Nerve - metabolism

Details

Title: Subtitle: ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load
Creators: Ramesh B Kasetti - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA
Pinkal D Patel - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA
Prabhavathi Maddineni - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA
Shruti Patil - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA
Charles Kiehlbauch - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA
J Cameron Millar - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA
Charles C Searby - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
VijayKrishna Raghunathan - Department of Biomedical Engineering, Cullen College of Engineering, University of Houston, Houston, TX, USA
Val C Sheffield - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Gulab S Zode - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA. gulab.zode@unthsc.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.11(1), pp.5594-5594
DOI: 10.1038/s41467-020-19352-1
PMID: 33154371
PMCID: PMC7644693
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 EY028616 / NEI NIH HHS R01 EY026177 / NEI NIH HHS R01 EY030366 / NEI NIH HHS
Language: English
Date published: 11/05/2020
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9984070312302771

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