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Cell Rep. 2017 Dec 5;21(10):2895-2910. doi: 10.1016/j.celrep.2017.11.027.

GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells.

Author information

1
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: dmk102@case.edu.
2
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
3
Department of Ophthalmology and Visual Science, Case Western Reserve University, Cleveland, OH 44106, USA.
4
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
5
Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
6
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
7
Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
8
Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: axb811@case.edu.
9
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: mxh8@case.edu.

Abstract

GADD34, a stress-induced regulatory subunit of the phosphatase PP1, is known to function in hyperosmotic stress through its well-known role in the integrated stress response (ISR) pathway. Adaptation to hyperosmotic stress is important for the health of corneal epithelial cells exposed to changes in extracellular osmolarity, with maladaptation leading to dry eye syndrome. This adaptation includes induction of SNAT2, an endoplasmic reticulum (ER)-Golgi-processed protein, which helps to reverse the stress-induced loss of cell volume and promote homeostasis through amino acid uptake. Here, we show that GADD34 promotes the processing of proteins synthesized on the ER during hyperosmotic stress independent of its action in the ISR. We show that GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation and is important for cis- to trans-Golgi trafficking of SNAT2, thereby promoting SNAT2 plasma membrane localization and function. These results suggest that GADD34 is a protective molecule for ocular diseases such as dry eye syndrome.

KEYWORDS:

GADD34; Golgi fragmentation; ISR; SNAT2; amino acid transport; hyperosmotic stress

PMID:
29212034
PMCID:
PMC5720379
DOI:
10.1016/j.celrep.2017.11.027
[Indexed for MEDLINE]
Free PMC Article

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