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GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis
Jian Wang1, Alton B Farris2, Kaiming Xu1
1Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
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.
Insights
G protein-coupled receptor class C group 5 member A (GPRC5A) suppresses oncogene synthesis, including EGFR, at the endoplasmic reticulum. Loss of GPRC5A enhances translation, promoting lung tumorigenesis, especially after radiation.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- G protein-coupled receptor class C group 5 member A (GPRC5A) is recognized for its role in preventing lung cancer.
- The precise molecular mechanisms underlying GPRC5A's tumor-suppressive function, particularly in response to environmental factors like ionizing radiation, are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which GPRC5A suppresses lung tumorigenesis.
- To investigate the role of GPRC5A in regulating protein synthesis and oncogene expression.
- To determine the impact of GPRC5A on radiation-induced lung cancer.
Main Methods:
- Investigated GPRC5A localization at the endoplasmic reticulum (ER) membrane.
- Analyzed GPRC5A's interaction with the eIF4F translation initiation complex.
- Assessed the impact of GPRC5A on the synthesis of secreted and membrane-bound proteins, including EGFR.
- Utilized Gprc5a knockout mice to study the effects of GPRC5A deletion on ionizing radiation (IR)-induced lung tumorigenesis and EGFR expression.
Main Results:
- GPRC5A localizes to the ER and suppresses the synthesis of key oncogenes, most notably EGFR, by disrupting the eIF4F translation initiation complex.
- GPRC5A's suppression of EGFR is crucial in preventing lung tumorigenesis induced by ionizing radiation.
- GPRC5A deficiency leads to enhanced EGFR translation and increased lung tumor incidence in mice exposed to IR.
- Under-expressed GPRC5A in lung tumors potentiates transcriptional stimulation via enhanced translation, promoting oncogene expression.
Conclusions:
- GPRC5A acts as a critical regulator of protein synthesis at the ER, specifically targeting oncogenes like EGFR.
- The loss of GPRC5A function promotes lung tumorigenesis by increasing EGFR translation, particularly in the context of IR exposure.
- Targeting GPRC5A-mediated translational control offers a potential strategy for managing oncogene expression and related diseases.
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