Tbc1d17, also known as Tre-2/Bub2/Cdc16 domain 1 family member 17, is a GTPase activating protein (GAP). It is involved in multiple biological processes such as glucose uptake, mitophagy, and membrane trafficking. In the glucose uptake pathway, it links AMPK and Rab5, with AMPK-mediated phosphorylation enhancing its auto-inhibition to promote Rab5-dependent glucose uptake [2]. In mitophagy, it is identified as a hub gene associated with vitiligo, suggesting its role in the disease's pathogenesis through immune infiltration [1].

In terms of membrane trafficking, Tbc1d17 regulates Rab8-mediated endocytic recycling of transferrin receptor. Optineurin (OPTN) mediates the interaction between Tbc1d17 and Rab8. A glaucoma-associated mutant of OPTN, E50K, enhances the inhibition of Rab8 by Tbc1d17, leading to defective endocytic recycling and autophagy impairment in retinal cells [3,4,5]. Tbc1d17 also forms homodimers and heterodimers with Tbc1d15, participating in mitophagy by regulating Rab7 activity at the interface between mitochondria and isolation membranes [6].

In conclusion, Tbc1d17 plays crucial roles in glucose homeostasis, mitophagy, and membrane trafficking. Its dysregulation is associated with diseases like vitiligo and glaucoma. Research on Tbc1d17 using genetic models helps to understand the underlying mechanisms of these biological processes and diseases, providing potential targets for treatment.

References:

1. Luo, Lingling, Zhu, Jing, Guo, Youming, Li, Chengrang. 2023. Mitophagy and immune infiltration in vitiligo: evidence from bioinformatics analysis. In Frontiers in immunology, 14, 1164124. doi:10.3389/fimmu.2023.1164124. https://pubmed.ncbi.nlm.nih.gov/37287971/

2. Rao, Xi Sheng, Cong, Xiao Xia, Gao, Xiu Kui, Zheng, Li Ling, Zhou, Yi Ting. 2021. AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake. In Cell death and differentiation, 28, 3214-3234. doi:10.1038/s41418-021-00809-9. https://pubmed.ncbi.nlm.nih.gov/34045668/

3. Chalasani, Madhavi Latha Somaraju, Kumari, Asha, Radha, Vegesna, Swarup, Ghanshyam. 2014. E50K-OPTN-induced retinal cell death involves the Rab GTPase-activating protein, TBC1D17 mediated block in autophagy. In PloS one, 9, e95758. doi:10.1371/journal.pone.0095758. https://pubmed.ncbi.nlm.nih.gov/24752605/

4. Vaibhava, Vipul, Nagabhushana, Ananthamurthy, Chalasani, Madhavi Latha Somaraju, Kumari, Asha, Swarup, Ghanshyam. 2012. Optineurin mediates a negative regulation of Rab8 by the GTPase-activating protein TBC1D17. In Journal of cell science, 125, 5026-39. doi:10.1242/jcs.102327. https://pubmed.ncbi.nlm.nih.gov/22854040/

5. Sirohi, Kapil, Swarup, Ghanshyam. 2015. Defects in autophagy caused by glaucoma-associated mutations in optineurin. In Experimental eye research, 144, 54-63. doi:10.1016/j.exer.2015.08.020. https://pubmed.ncbi.nlm.nih.gov/26302410/

6. Yamano, Koji, Fogel, Adam I, Wang, Chunxin, van der Bliek, Alexander M, Youle, Richard J. 2014. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. In eLife, 3, e01612. doi:10.7554/eLife.01612. https://pubmed.ncbi.nlm.nih.gov/24569479/