Rab21, a member of the Rab family of small GTPases, plays crucial roles in regulating intracellular transportation and cargo delivery [2]. It is involved in endosomal trafficking pathways, which are essential for maintaining cellular homeostasis, and has connections to processes like cell signaling, division, and survival [2].

Depletion of Rab21 in cancer cells mis-sorts the glucose transporter SLC2A1/GLUT1 to lysosomes, affecting glucose uptake, activating the AMPK-ULK1 pathway, and increasing autophagic flux and lysosome function. This sensitizes cancer cells to energy stress and inhibits tumor growth in vivo, suggesting an oncogenic role [1]. In enterocytes, Rab21 knockdown leads to intestinal morphology abnormalities, deregulated cellular equilibrium, increased apoptosis, and tissue inflammation [3]. In neurons, Rab21 is required for neuronal development and migration in the cerebral cortex. Loss of Rab21 function increases membrane-exposed amyloid precursor protein levels, impairing cortical neuronal differentiation and migration [4]. In macrophages and monocytes, Rab21 knockdown inhibits lipopolysaccharide (LPS)-induced pro-inflammatory cytokine production by affecting TLR4 endosomal traffic and downstream signaling activation [5].

In conclusion, Rab21 is essential for multiple biological processes such as maintaining cellular energy homeostasis, intestinal epithelium maintenance, neuronal development, and regulation of the immune response. Model-based research, especially loss-of-function experiments, has revealed its significant roles in diseases like cancer, neurodegenerative diseases, and inflammation, providing potential therapeutic targets in these disease areas.

References:

1. Pei, Yifei, Lv, Shuning, Shi, Yong, Tan, Jieqiong, Zhang, Xinjun. 2022. RAB21 controls autophagy and cellular energy homeostasis by regulating retromer-mediated recycling of SLC2A1/GLUT1. In Autophagy, 19, 1070-1086. doi:10.1080/15548627.2022.2114271. https://pubmed.ncbi.nlm.nih.gov/35993307/

2. Li, Xinjian, Ni, Junjun, Qing, Hong, Quan, Zhenzhen. 2023. The Regulatory Mechanism of Rab21 in Human Diseases. In Molecular neurobiology, 60, 5944-5953. doi:10.1007/s12035-023-03454-0. https://pubmed.ncbi.nlm.nih.gov/37369821/

3. Nassari, Sonya, Lacarrière-Keïta, Camille, Lévesque, Dominique, Boisvert, François-Michel, Jean, Steve. 2022. Rab21 in enterocytes participates in intestinal epithelium maintenance. In Molecular biology of the cell, 33, ar32. doi:10.1091/mbc.E21-03-0139. https://pubmed.ncbi.nlm.nih.gov/35171715/

4. Peralta Cuasolo, Yael Macarena, Dupraz, Sebastián, Unsain, Nicolas, Quiroga, Santiago, Sosa, Lucas Javier. 2023. The GTPase Rab21 is required for neuronal development and migration in the cerebral cortex. In Journal of neurochemistry, 166, 790-808. doi:10.1111/jnc.15925. https://pubmed.ncbi.nlm.nih.gov/37534523/

5. Li, Ping, Wu, Yong-Hong, Zhu, Yan-Ting, Li, Man-Xiang, Pei, Hong-Hong. 2018. Requirement of Rab21 in LPS-induced TLR4 signaling and pro-inflammatory responses in macrophages and monocytes. In Biochemical and biophysical research communications, 508, 169-176. doi:10.1016/j.bbrc.2018.11.074. https://pubmed.ncbi.nlm.nih.gov/30471852/