Rab27a, a member of the Rab GTPase family, is crucial for membrane trafficking processes. It exists in an 'active' GTP-bound and 'inactive' GDP-bound state, acting as a molecular switch. Rab27a is involved in pathways such as exosome secretion, insulin secretion in pancreatic β-cells, and immune cell function, thus being of great biological importance. Genetic models, like gene knockout (KO) mouse models, are valuable for studying its functions [2,3,6].

In exosome secretion, RNA interference (RNAi) screen showed that Rab27a functions in multivesicular endosome (MVE) docking at the plasma membrane, and its silencing strongly increased MVE size [1]. In pancreatic β-cells, Rab27a knockdown would disrupt the pre-exocytotic stages of insulin secretion regulated by its GTP-bound form and the endocytosis regulated by its GDP-bound form [2,3,6]. In colorectal cancer cells, RAB27A knockdown inhibited proliferation, clone formation, migration and invasion, indicating its oncogenic role [4]. In cerebral ischemic injury, Rab27a knockout (Rab27a-/-) mice had decreased exosome levels in brain tissue, increased infarct volume, and other negative effects, demonstrating Rab27a's role in protecting against cerebral ischemic injury via exosome-related mechanisms [5].

In conclusion, Rab27a plays essential roles in multiple biological processes such as exosome secretion, insulin secretion, and in disease-related cellular behaviors like cancer cell proliferation and invasion, as well as protection against cerebral ischemic injury. The use of KO mouse models has significantly contributed to understanding its role in these disease areas, providing insights into potential therapeutic targets and disease mechanisms.

References:

1. Ostrowski, Matias, Carmo, Nuno B, Krumeich, Sophie, Moita, Luis F, Thery, Clotilde. 2009. Rab27a and Rab27b control different steps of the exosome secretion pathway. In Nature cell biology, 12, 19-30; sup pp 1-13. doi:10.1038/ncb2000. https://pubmed.ncbi.nlm.nih.gov/19966785/

2. Kimura, Toshihide, Niki, Ichiro. 2010. Rab27a, actin and beta-cell endocytosis. In Endocrine journal, 58, 1-6. doi:. https://pubmed.ncbi.nlm.nih.gov/21187662/

3. Yamaoka, Mami, Ishizaki, Toshimasa, Kimura, Toshihide. . Interplay between Rab27a effectors in pancreatic β-cells. In World journal of diabetes, 6, 508-16. doi:10.4239/wjd.v6.i3.508. https://pubmed.ncbi.nlm.nih.gov/25897360/

4. Li, Qingyan, Zhao, Huixia, Dong, Weiwei, Yang, Jingwen, Xiao, Wenhua. 2022. RAB27A promotes the proliferation and invasion of colorectal cancer cells. In Scientific reports, 12, 19359. doi:10.1038/s41598-022-23696-7. https://pubmed.ncbi.nlm.nih.gov/36371494/

5. Ma, Xiaotang, Zhao, Jia, Li, Suqing, Chen, Yanfang, Pan, Qunwen. 2022. Rab27a-dependent exosomes protect against cerebral ischemic injury by reducing endothelial oxidative stress and apoptosis. In CNS neuroscience & therapeutics, 28, 1596-1612. doi:10.1111/cns.13902. https://pubmed.ncbi.nlm.nih.gov/35770324/

6. Kimura, Toshihide, Niki, Ichiro. 2011. Rab27a in pancreatic beta-cells, a busy protein in membrane trafficking. In Progress in biophysics and molecular biology, 107, 219-23. doi:10.1016/j.pbiomolbio.2011.06.016. https://pubmed.ncbi.nlm.nih.gov/21762718/