Vps29-KO Mouse

Vps29, short for vacuolar protein sorting 29, is a key component of the retromer complex. The retromer complex is involved in the endosome-to-Golgi retrieval cargo transport pathway, and Vps29 plays a crucial role in coordinating the physical assembly of retrieval complexes with regulatory components, thus being essential for endosomal recycling [1,4,5,6,8]. This process is vital for maintaining the proteostatic plasticity of the cell under variable physiological demands [1].

In Drosophila, Vps29 is dispensable for embryogenesis but required for retromer function in aging adults. Vps29 mutants show mislocalization of retromer from neuropil to soma with the Rab7 GTPase, leading to progressive endolysosomal dysfunction, impaired substrate clearance, and lysosomal stress, highlighting its role in brain homeostasis during aging [6]. In human lung cell lines, a loss-of-function genome-wide CRISPR screen showed that Vps29 is required for the infection of several coronaviruses including SARS-CoV-2 and ebolavirus, while it has an enhancing effect on influenza A virus infection. Deficiency in Vps29 causes changes in endosome morphology and acidity and attenuates endosomal protease activity, entrapping incoming coronavirus particles [2]. In a human iPSC-derived neuronal model of 4R tauopathy, a CRISPRi screen identified Vps29 as a genetic modifier of seeding-induced Tau propagation [3]. A bioinformatics and Mendelian randomization study indicated that Vps29 is overexpressed in hepatocellular carcinoma (HCC), is an independent prognostic factor, and is associated with an increased risk of HCC [7].

In conclusion, Vps29 is integral to endosomal recycling, which is essential for normal cellular function. Model-based research, such as in Drosophila and human cell lines, has revealed its significance in various disease-related processes, including viral infections, neurodegenerative diseases like tauopathy, and cancer, specifically HCC. Understanding Vps29's function through these models provides insights into potential therapeutic targets for these diseases.