Rgs10, short for Regulator of G protein signaling-10, is a GTPase-activating protein (GAP) for Gαi3, Gαq, and Gαz. It belongs to the D/R12 subfamily based on RGS domain homology and is one of the smallest RGS proteins outside the RGS box. Rgs10 can be palmitoylated to target to the membrane, increasing its GAP activity. It is also phosphorylated by protein kinase A at Ser(168), promoting its translocation from the cytosol to the nucleus. Besides its GAP function, it modulates adenylyl cyclase activity and G protein-gated inwardly rectifying potassium channels [1].

In various disease models, Rgs10 has shown important roles. In breast cancer, Rgs10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition, with lower Rgs10 protein levels in cancer tissues predicting a worse prognosis [2]. In microglia, Rgs10 mitigates high glucose-induced inflammation via the reactive oxidative stress pathway and enhances synuclein clearance. Rgs10-deficient mice exhibit impaired glucose tolerance and insulin resistance [3]. In a mouse model of influenza, Rgs10-deficient mice experience enhanced weight loss, higher lung viral titers, and mortality, as Rgs10 negatively modulates lung immune and inflammatory responses [4]. In colorectal carcinoma, Rgs10 expression is suppressed by DNA methylation, associated with low survival rates [5]. In Parkinson's disease, Rgs10 levels are decreased in the cerebrospinal fluid of patients, and Rgs10 deficiency synergizes with chronic systemic inflammation to induce immune cell dysregulation [6,7]. In pulmonary hypertension, Rgs10 inhibits the proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/mTORC1 signaling pathway [8]. In apical periodontitis, local overexpression of Rgs10 reduces alveolar bone destruction and macrophage infiltration, suppressing the inflammatory response through TFEB-mediated autophagy [9]. In periodontitis with rheumatoid arthritis, inhibition of Rgs10 in mice promotes the progression of periodontitis [10].

In conclusion, Rgs10 plays essential roles in multiple biological processes and disease conditions. Through gene knockout (KO) or conditional knockout (CKO) mouse models and other loss-of-function experiments, it has been revealed that Rgs10 is involved in regulating immune responses, inflammation, cell proliferation, and metastasis, contributing significantly to our understanding of diseases such as cancer, neurodegenerative diseases, and inflammatory diseases.

References:

1. Lee, Jae-Kyung, Tansey, Malú G. 2015. Physiology of RGS10 in Neurons and Immune Cells. In Progress in molecular biology and translational science, 133, 153-67. doi:10.1016/bs.pmbts.2015.01.005. https://pubmed.ncbi.nlm.nih.gov/26123306/

2. Liu, Yang, Jiang, Yi, Qiu, Peng, Zhu, Tong, Gu, Xi. 2024. RGS10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition in breast cancer. In eLife, 13, . doi:10.7554/eLife.97327. https://pubmed.ncbi.nlm.nih.gov/39145770/

3. Chung, Jaegwon, Jernigan, Janna, Menees, Kelly B, Lee, Jae-Kyung. 2024. RGS10 mitigates high glucose-induced microglial inflammation via the reactive oxidative stress pathway and enhances synuclein clearance in microglia. In Frontiers in cellular neuroscience, 18, 1374298. doi:10.3389/fncel.2024.1374298. https://pubmed.ncbi.nlm.nih.gov/38812790/

4. Almutairi, Faris, Sarr, Demba, Tucker, Samantha L, Lee, Jae-Kyung, Rada, Balázs. 2021. RGS10 Reduces Lethal Influenza Infection and Associated Lung Inflammation in Mice. In Frontiers in immunology, 12, 772288. doi:10.3389/fimmu.2021.772288. https://pubmed.ncbi.nlm.nih.gov/34912341/

5. Caldiran, Feyzanur Yildirimtepe, Cacan, Ercan. 2022. RGS10 suppression by DNA methylation is associated with low survival rates in colorectal carcinoma. In Pathology, research and practice, 236, 154007. doi:10.1016/j.prp.2022.154007. https://pubmed.ncbi.nlm.nih.gov/35810565/

6. Jernigan, Janna E, Staley, Hannah A, Baty, Zachary, Coombes, Stephen A, Tansey, Malú Gámez. 2025. RGS10 attenuates systemic immune dysregulation induced by chronic inflammatory stress. In Journal of neuroinflammation, 22, 49. doi:10.1186/s12974-024-03322-1. https://pubmed.ncbi.nlm.nih.gov/39994765/

7. Jernigan, Janna E, Staley, Hannah A, Baty, Zachary, Coombes, Stephen A, Tansey, Malú Gámez. 2024. RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.10.24.620078. https://pubmed.ncbi.nlm.nih.gov/39554164/

8. Hu, Sheng, Zhang, Yijie, Qiu, Chenming, Li, Ying. 2023. RGS10 inhibits proliferation and migration of pulmonary arterial smooth muscle cell in pulmonary hypertension via AKT/mTORC1 signaling. In Clinical and experimental hypertension (New York, N.Y. : 1993), 45, 2271186. doi:10.1080/10641963.2023.2271186. https://pubmed.ncbi.nlm.nih.gov/37879890/

9. Li, Jiaxin, Yue, Yuan, Chan, Weicheng, Li, Jinle, Hao, Liang. 2023. RGS10 negatively regulates apical periodontitis via TFEB-mediated autophagy in BABL/c mice model and in vitro. In International endodontic journal, 56, 854-868. doi:10.1111/iej.13924. https://pubmed.ncbi.nlm.nih.gov/37092953/

10. Chan, Wei-Cheng, Tan, Liangyu, Liu, Jie, Hao, Liang, Man, Yi. 2022. Inhibition of Rgs10 aggravates periodontitis with collagen-induced arthritis via the nuclear factor-κB pathway. In Oral diseases, 29, 1802-1811. doi:10.1111/odi.14147. https://pubmed.ncbi.nlm.nih.gov/35122384/