Rab5a, a member of the Rab small GTPase family, is crucial for early endosome biogenesis and autophagy initiation [5]. It is involved in multiple cellular processes such as vesicle trafficking, endocytosis, and cell signaling, playing a significant role in maintaining normal cellular functions and physiological processes [2,3,4,5]. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, have been valuable in studying its functions.

In various disease conditions, Rab5a has shown distinct impacts. In postinfectious irritable bowel syndrome (PI-IBS), Rab5a promotes cytolethal distending toxin B (CdtB)-induced cytotoxicity in colonic epithelial cells and proinflammatory responses in macrophages, as Rab5a silencing or knockout largely inhibits CdtB-related effects [1]. In rheumatoid arthritis, Fusobacterium nucleatum aggravates the disease through outer membrane vesicles containing FadA, which activates Rab5a in synovial macrophages, triggering local inflammatory responses [2]. Also, in Alzheimer's disease (AD), Rab5a hyperactivation is an early pathological manifestation, and electroacupuncture can suppress Rab5a-GTP to promote nerve growth factor (NGF) signaling transduction, improving cognitive impairment in the early stage of AD mice [3]. In muscle regeneration, myogenic Rab5a-deficient mice reveal that Rab5a is essential for regulating skeletal muscle regeneration, as it promotes myoblast differentiation and coordinates IGF-AKT-mTOR signaling by interacting with insulin receptor substrate 1 (IRS1) [4].

In conclusion, Rab5a is essential for multiple cellular and physiological processes. KO/CKO mouse models have helped uncover its roles in diseases such as PI-IBS, rheumatoid arthritis, AD, and muscle-related conditions. Understanding Rab5a's functions provides insights into disease mechanisms and potential therapeutic targets for these diseases.

References:

1. Chen, Ming-Xian, Chen, Yu, Fu, Rui, Liu, Sai-Yue, Shen, Tang-Biao. 2020. Rab5a Promotes Cytolethal Distending Toxin B-Induced Cytotoxicity and Inflammation. In Infection and immunity, 88, . doi:10.1128/IAI.00132-20. https://pubmed.ncbi.nlm.nih.gov/32747601/

2. Hong, Mukeng, Li, Zhuang, Liu, Haihua, Zhou, Hongwei, Li, Juan. 2023. Fusobacterium nucleatum aggravates rheumatoid arthritis through FadA-containing outer membrane vesicles. In Cell host & microbe, 31, 798-810.e7. doi:10.1016/j.chom.2023.03.018. https://pubmed.ncbi.nlm.nih.gov/37054714/

3. Li, Jianhong, Yang, Minguang, Dai, Yaling, Tao, Jing, Liu, Weilin. . Electroacupuncture regulates Rab5a-mediating NGF transduction to improve learning and memory ability in the early stage of AD mice. In CNS neuroscience & therapeutics, 30, e14743. doi:10.1111/cns.14743. https://pubmed.ncbi.nlm.nih.gov/38780008/

4. Cong, Xiao Xia, Gao, Xiu Kui, Rao, Xi Sheng, Zheng, Li Ling, Zhou, Yi Ting. 2020. Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration. In Cell death and differentiation, 27, 2344-2362. doi:10.1038/s41418-020-0508-1. https://pubmed.ncbi.nlm.nih.gov/32051546/

5. Zhao, Zhenyu, Wei, Zhen, Zheng, Jiaxin, Lu, Mengji, Lin, Yong. 2023. Hepatitis B virus promotes its own replication by enhancing RAB5A-mediated dual activation of endosomal and autophagic vesicle pathways. In Emerging microbes & infections, 12, 2261556. doi:10.1080/22221751.2023.2261556. https://pubmed.ncbi.nlm.nih.gov/37725090/