Snx9, or sorting nexin-9, is a multifunctional scaffold protein. It is significantly involved in membrane trafficking and remodeling, coordinating these processes with changes in actin dynamics. It participates in various cellular activities such as endocytosis, with a particular role in clathrin-mediated endocytosis, where it binds strongly to dynamin, recruits it to endocytic sites, stimulates its GTPase activity for vesicle scission, and can activate N-WASP for actin polymerization during vesicle release [2,3,5].

In cancer immunotherapy, gene knockout studies showed that deletion of Snx9 in CD8 T cells alleviates T cell exhaustion. It decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling, reduces expression of NR4A1/3 and TOX, enhances memory differentiation and IFNγ secretion of adoptively transferred T cells, and improves the anti-tumor efficacy of human chimeric antigen receptor T cells in vivo [1]. In autosomal dominant polycystic kidney disease (ADPKD), Snx9 expression is downregulated. Ectopic expression of Snx9 inhibits ADPKD cell proliferation and cyst formation by interacting with yes-associated protein (YAP) and activating the Hippo-YAP signaling pathway, while Snx9 silencing promotes these effects [4].

In conclusion, Snx9 is crucial for multiple cellular functions, especially those related to membrane-associated events and actin regulation. Gene knockout models have revealed its significance in T cell-mediated anti-tumor immunity and in the pathogenesis of ADPKD, providing potential therapeutic targets for cancer immunotherapy and ADPKD treatment.

References:

1. Trefny, Marcel P, Kirchhammer, Nicole, Auf der Maur, Priska, Hess, Christoph, Zippelius, Alfred. 2023. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy. In Nature communications, 14, 86. doi:10.1038/s41467-022-35583-w. https://pubmed.ncbi.nlm.nih.gov/36732507/

2. Lundmark, Richard, Carlsson, Sven R. . SNX9 - a prelude to vesicle release. In Journal of cell science, 122, 5-11. doi:10.1242/jcs.037135. https://pubmed.ncbi.nlm.nih.gov/19092055/

3. Bendris, Nawal, Schmid, Sandra L. 2016. Endocytosis, Metastasis and Beyond: Multiple Facets of SNX9. In Trends in cell biology, 27, 189-200. doi:10.1016/j.tcb.2016.11.001. https://pubmed.ncbi.nlm.nih.gov/27989654/

4. Shen, Ai-Wen, Fu, Li-Li, Lin, Lu, Yin, Pei-Ran, Yu, Sheng-Qiang. 2020. SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway. In Frontiers in cell and developmental biology, 8, 811. doi:10.3389/fcell.2020.00811. https://pubmed.ncbi.nlm.nih.gov/32974348/

5. Soulet, Fabienne, Yarar, Defne, Leonard, Marilyn, Schmid, Sandra L. 2005. SNX9 regulates dynamin assembly and is required for efficient clathrin-mediated endocytosis. In Molecular biology of the cell, 16, 2058-67. doi:. https://pubmed.ncbi.nlm.nih.gov/15703209/