Ric8b, a member of the Resistance to inhibitors of cholinesterase 8 protein family, acts as a non-receptor guanine nucleotide exchange factor (GEF) and molecular chaperone for heterotrimeric G-protein α subunits [5,6]. It is involved in multiple signaling pathways, such as those related to G-protein-coupled receptor (GPCR) signaling, and is crucial for normal development, cellular growth, and differentiation [3].

Elp3, an enzyme in the Elongator complex, promotes mTORC2 activation by enhancing the translation of Ric8b in a codon-dependent manner, which in turn regulates macrophage polarization [1]. In testicular Sertoli cells of primates, low levels of Ric8b and Gαs may be responsible for the restricted FSH action during infancy [4]. In GNAO1 encephalopathies, pathogenic Gαo mutants gain interaction with Ric8B, relocalizing it from the cytoplasm to the Golgi, and the strength of this interaction correlates with disease severity [2].

In summary, Ric8b plays essential roles in macrophage polarization, FSH-related testicular function, and is associated with GNAO1 encephalopathies. Research on Ric8b, especially through in vivo models like gene knockout or conditional knockout mouse models, helps to understand its functions in these biological processes and disease conditions, providing insights into potential disease mechanisms and therapeutic targets.

References:

1. Chen, Dawei, Nemazanyy, Ivan, Peulen, Olivier, Dewals, Benjamin, Chariot, Alain. 2022. Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization. In The EMBO journal, 41, e109353. doi:10.15252/embj.2021109353. https://pubmed.ncbi.nlm.nih.gov/35920020/

2. Solis, Gonzalo P, Koval, Alexey, Valnohova, Jana, Savitsky, Mikhail, Katanaev, Vladimir L. 2024. Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies. In The Journal of clinical investigation, 134, . doi:10.1172/JCI172057. https://pubmed.ncbi.nlm.nih.gov/38874642/

3. Maureira, Alejandro, Sánchez, Rodolfo, Valenzuela, Nicole, Olate, Juan, Gutiérrez, José L. 2016. The CREB Transcription Factor Controls Transcriptional Activity of the Human RIC8B Gene. In Journal of cellular biochemistry, 117, 1797-805. doi:10.1002/jcb.25479. https://pubmed.ncbi.nlm.nih.gov/26729411/

4. Bhattacharya, Indrashis, Basu, Sayon, Sarda, Kanchan, Devi, Yendrembam Sangeeta, Majumdar, Subeer S. 2014. Low levels of Gαs and Ric8b in testicular sertoli cells may underlie restricted FSH action during infancy in primates. In Endocrinology, 156, 1143-55. doi:10.1210/en.2014-1746. https://pubmed.ncbi.nlm.nih.gov/25549048/

5. Tall, Gregory G. 2013. Ric-8 regulation of heterotrimeric G proteins. In Journal of receptor and signal transduction research, 33, 139-43. doi:10.3109/10799893.2013.763828. https://pubmed.ncbi.nlm.nih.gov/23384070/

6. Hinrichs, M V, Torrejón, M, Montecino, M, Olate, J. . Ric-8: different cellular roles for a heterotrimeric G-protein GEF. In Journal of cellular biochemistry, 113, 2797-805. doi:10.1002/jcb.24162. https://pubmed.ncbi.nlm.nih.gov/22511245/