GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis

Jian Wang, Alton B. Farris, Kaiming Xu, Ping Wang, Xiangming Zhang, Duc M. Duong, Hong Yi, Hui-Kuo Shu, Shi-Yong Sun and Ya Wang ()
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Jian Wang: Emory University School of Medicine and the Winship Cancer Institute, Emory University
Alton B. Farris: Emory University School of Medicine and the Winship Cancer Institute, Emory University
Kaiming Xu: Emory University School of Medicine and the Winship Cancer Institute, Emory University
Ping Wang: Emory University School of Medicine and the Winship Cancer Institute, Emory University
Xiangming Zhang: Emory University School of Medicine and the Winship Cancer Institute, Emory University
Duc M. Duong: Emory Integrated Proteomics Core and Biochemistry Department
Hong Yi: Robert P. Apkaran Integrated Electron Microscope Core, Emory University
Hui-Kuo Shu: Emory University School of Medicine and the Winship Cancer Institute, Emory University
Shi-Yong Sun: Emory University School of Medicine and the Winship Cancer Institute
Ya Wang: Emory University School of Medicine and the Winship Cancer Institute, Emory University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; however, the underlying mechanism remains unclear. Here we reveal that GPRC5A at the endoplasmic reticulum (ER) membrane suppresses synthesis of the secreted or membrane-bound proteins including a number of oncogenes, the most important one being Egfr. The ER-located GPRC5A disturbs the assembly of the eIF4F-mediated translation initiation complex on the mRNA cap through directly binding to the eIF4F complex with its two middle extracellular loops. Particularly, suppression of EGFR by GPRC5A contributes significantly to preventing ionizing radiation (IR)-induced lung tumorigenesis. Thus, GPRC5A deletion enhances IR-promoted EGFR expression through an increased translation rate, thereby significantly increasing lung tumour incidence in Gprc5a−/− mice. Our findings indicate that under-expressed GPRC5A during lung tumorigenesis enhances any transcriptional stimulation through an active translational status, which can be used to control oncogene expression and potentially the resulting related disease.

Date: 2016
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DOI: 10.1038/ncomms11795

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