Vps29-KO Mouse

Vps29, a component of the retromer complex, is crucial for endosomal recycling. The endolysosomal system, where Vps29 functions, is a dynamic membrane network for degradation and recycling. Vps29 serves as a central scaffold, coordinating the assembly of retrieval complexes with regulatory components to maintain the balance between degradation and recycling in cells [1].

Loss-of-function studies have revealed diverse roles of Vps29. A CRISPR screen showed that Vps29 is required for the infection of several coronaviruses, including SARS-CoV-2, and ebolavirus, but has an enhancing effect on influenza A virus infection. Deficiency in Vps29 causes changes in endosome morphology, acidity, and attenuates endosomal protease activity, entrapping incoming coronavirus particles [2]. In Drosophila, Vps29 is dispensable for embryogenesis but essential for retromer function in aging adults, regulating synaptic transmission, survival, and locomotion. In Vps29 mutants, retromer is mislocalized, and with aging, it triggers endolysosomal dysfunction [4]. A CRISPRi screen in a human iPSC-derived neuronal model identified Vps29 as a genetic modifier of seeding-induced Tau propagation in tauopathies [3]. Bioinformatics and Mendelian randomization analysis indicated that Vps29 is overexpressed in hepatocellular carcinoma (HCC), is an independent prognostic factor, and a risk factor for HCC occurrence and progression [5].

In summary, Vps29 plays essential roles in endosomal recycling, which is vital for maintaining cellular homeostasis. Its functions have been linked to viral infections, neurodegenerative diseases like tauopathies, and cancer, especially HCC. Studies using loss-of-function models such as Drosophila mutants and CRISPR-based screens in cell lines have been instrumental in uncovering these roles, providing insights into potential therapeutic targets for related diseases.

References:

1. Baños-Mateos, Soledad, Rojas, Adriana L, Hierro, Aitor. 2019. VPS29, a tweak tool of endosomal recycling. In Current opinion in cell biology, 59, 81-87. doi:10.1016/j.ceb.2019.03.010. https://pubmed.ncbi.nlm.nih.gov/31051431/

2. Poston, Daniel, Weisblum, Yiska, Hobbs, Alvaro, Bieniasz, Paul D. 2022. VPS29 Exerts Opposing Effects on Endocytic Viral Entry. In mBio, 13, e0300221. doi:10.1128/mbio.03002-21. https://pubmed.ncbi.nlm.nih.gov/35229640/

3. Parra Bravo, Celeste, Giani, Alice Maria, Madero-Perez, Jesus, Gong, Shiaoching, Gan, Li. 2024. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. In Cell, 187, 2446-2464.e22. doi:10.1016/j.cell.2024.03.015. https://pubmed.ncbi.nlm.nih.gov/38582079/

4. Ye, Hui, Ojelade, Shamsideen A, Li-Kroeger, David, Bellen, Hugo J, Shulman, Joshua M. 2020. Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain. In eLife, 9, . doi:10.7554/eLife.51977. https://pubmed.ncbi.nlm.nih.gov/32286230/

5. Yao, Y-Q, Lv, J-L. . Potential functions and causal associations of VPS29 in hepatocellular carcinoma: a bioinformatic and Mendelian randomization study. In European review for medical and pharmacological sciences, 27, 9586-9600. doi:10.26355/eurrev_202310_34131. https://pubmed.ncbi.nlm.nih.gov/37916325/