Rho guanine nucleotide exchange factor (RGNEF) is a prosurvival factor under stress conditions

Kevin Cheung; Cristian A Droppelmann; Adam MacLellan; Ian Cameron; Benjamin Withers; Danae Campos-Melo; Kathryn Volkening; Michael J Strong

doi:10.1016/j.mcn.2017.05.003

Rho guanine nucleotide exchange factor (RGNEF) is a prosurvival factor under stress conditions

Mol Cell Neurosci. 2017 Jul:82:88-95. doi: 10.1016/j.mcn.2017.05.003. Epub 2017 May 8.

Authors

Kevin Cheung¹, Cristian A Droppelmann², Adam MacLellan², Ian Cameron², Benjamin Withers², Danae Campos-Melo², Kathryn Volkening³, Michael J Strong⁴

Affiliations

¹ Department of Pathology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada; Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada.
² Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada.
³ Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada; Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada.
⁴ Department of Pathology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada; Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada; Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 5K8, Canada. Electronic address: michael.strong@schulich.uwo.ca.

PMID: 28495450
DOI: 10.1016/j.mcn.2017.05.003

Abstract

Rho guanine nucleotide exchange factor (RGNEF) is a 190kDa RNA binding protein (RBP) that also contains a Dbl/PH domain capable of RhoA activation. Consistent with a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS), RGNEF forms pathological neuronal cytoplasmic inclusions in degenerating spinal motor neurons. To further understand the role of RGNEF in the stress response, we first observed that the expression of RGNEF is upregulated in murine spinal motor neurons following distal sciatic nerve injury. Secondly, in response to in vitro cellular stress (500μM sodium arsenite for 1h; or 400mM sorbitol 1 hour exposure; as an oxidative or osmotic stress, respectively), we observed a significant survival benefit in RGNEF-transfected HEK293T cells. Using deletion constructs, we found that the NH₂-terminus domain is essential for this protective effect. Interestingly, we observed that under stress conditions RGNEF associates with Staufen1 positive granules but not TIA-1-positive stress granules. These findings support the hypothesis that RGNEF plays a critical role both in RNA homeostasis and in the response to cell stress.

Keywords: ALS; Axonal injury; Osmotic stress; Oxidative stress; RGNEF; Staufen; Stress granule.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics*
Animals
Arsenites / pharmacology
HEK293 Cells
Homeostasis / physiology
Humans
Inclusion Bodies / metabolism
Mice, Inbred C57BL
Motor Neurons / metabolism*
RNA / metabolism
Sodium Compounds / pharmacology
Stress, Physiological*
ras-GRF1 / metabolism*

Substances

Arsenites
Rasgrf1 protein, mouse
Sodium Compounds
ras-GRF1
sodium arsenite
RNA

Grants and funding

325745/CIHR/Canada