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

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.

Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin

“…These findings further support our conclusion that reduction of CHOP reduces mutant myocilin via promoting autophagic degradation of mutant myocilin. We have recently shown that chronic ER stress induced ATF4, and CHOP promoted increased protein synthesis, which leads to ER client protein load ( 43 ). It is therefore possible that chronic ER stress–induced protein synthesis and ER client protein load may overwhelm autophagy.…”

“…TM3 cells stably expressing DsRed-tagged WT or mutant (Y437H, G364V and Q368X) myocilin were generated by transfecting with plasmid expressing DsRedtagged WT or mutant (Y437H, G364V and Q368X) myocilin containing a G418 selection. The stable cell colonies were then selected using G418 (0.6 mg/ml; Gibco, Life Technologies, Grand Island, NY, USA) containing media and stable cells were maintained in the same medium as described previously (43,68).…”

“…It is not understood why autophagy fails to degrade mutant myocilin and whether autophagy plays a critical role in mutant myocilin–induced ocular hypertension. We have recently shown that induction of chronic ER stress leads to glaucoma by increasing protein synthesis and ER client protein load in TM cells ( 43 ). These events can further lead to compromised autophagy.…”

Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma

“…Zode et al [ 22 ] reported that, the transcriptional factor C/EBP homologous protein (CHOP), a marker for chronic endoplasmic reticulum (ER) stress, is upregulated in the anterior segment tissues, and CHOP deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Additionally, Kasetti et al have also reported that [ 23 ] activating transcription factor 4 (ATF4)- C/EBP homologous protein (CHOP)– growth arrest and DNA damage-inducible protein (GADD34) signaling pathway is induced in the glaucomatous TM, and that induction of these proteins is associated with IOP elevation in dexamethasone-acetate (Dex-Ac) induced OHT mice and ROS production in glaucomatous human TM cells. ATF4 levels are found to be elevated in the TM tissues of 5-week Dex-treated mice [ 23 ], indicating that this model may appropriately recapitulate the glaucoma pathology due to ROS elevation, and SA-9 may able to scavenge them.…”

Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma

“…Both PERK and IRE1α are type I transmembrane proteins with similar ER luminal domain structures and a cytosolic Serine/threonine kinase domain, whereas ATF6α is a type II transmembrane protein that contains a cytosolic cyclic AMP response element-binding protein (CREB)–ATF basic leucine zipper domain [ 31 , 32 , 33 , 34 ]. IRE1α, PERK, ATF6 and CREBH are ultimately responsible for the activation of a set of transcription factors (TF), including spliced X-box binding protein 1 (XBP1s), activating transcription factor 4 (ATF4), CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP), nuclear factor κB (NF-κB) and activator protein 1 (AP-1), through a complicated and nonparallel process [ 35 , 36 , 37 , 38 , 39 ].…”