Slc15a2, also known as PEPT2, encodes the cell membrane proton-coupled peptide transporter 2. It plays a pivotal role in numerous biological processes, including the transport of various substances such as bacterially derived di/tripeptides, nephrotoxic drugs like colistin, and some antibiotics like cefadroxil [3,4,5,6]. It is involved in pathways related to cell proliferation, adhesion, lipid metabolism, and also has implications in protein synthesis, degradation, RNA metabolism, and energy metabolism [1].

In prostate cancer, low expression of Slc15a2 was associated with early biochemical recurrence and decreased overall survival, and knockdown of Slc15a2 enhanced the proliferation and migratory capacity of PCa cells [1]. In the context of radiation-induced hematopoietic stem cell injury, exercise-generated carnosine is transported to HSCs via Slc15a2, which then inhibits p53 transcriptional activity, promoting the proliferation and survival of irradiated HSCs [2]. In kidney disease, SLC15A2 was upregulated in the tubulointerstitium of human CKD, and cefadroxil targeting SLC15A2 protected from colistin nephrotoxicity [3].

In summary, Slc15a2 is crucial for the transport of multiple substances and is involved in various biological processes. Gene-knockout or knockdown studies in different disease models, such as in prostate cancer, radiation-induced hematopoietic injury, and kidney disease, have revealed its role in disease development and progression, highlighting its potential as a therapeutic target and prognostic biomarker.

References:

1. Yin, Wenjun, He, Pingkaiqi, Zou, Zhihao, Lu, Jianming, Zhong, Weide. 2024. SLC15A2 Serves as a Novel Prognostic Biomarker and Target for Prostate Cancer. In Anticancer research, 45, 153-172. doi:10.21873/anticanres.17402. https://pubmed.ncbi.nlm.nih.gov/39740843/

2. Zeng, Hao, Chen, Naicheng, Chen, Fang, Wang, Junping, Hu, Mengjia. 2024. Exercise alleviates hematopoietic stem cell injury following radiation via the carnosine/Slc15a2-p53 axis. In Cell communication and signaling : CCS, 22, 582. doi:10.1186/s12964-024-01959-2. https://pubmed.ncbi.nlm.nih.gov/39627813/

3. Fernandez-Prado, Raul, Valiño, Lara, Pintor-Chocano, Aranzazu, Ortiz, Alberto, Sanchez-Niño, Maria Dolores. 2024. Cefadroxil Targeting of SLC15A2/PEPT2 Protects From Colistin Nephrotoxicity. In Laboratory investigation; a journal of technical methods and pathology, 105, 102182. doi:10.1016/j.labinv.2024.102182. https://pubmed.ncbi.nlm.nih.gov/39522761/

4. Hu, Yongjun, Song, Feifeng, Jiang, Huidi, Nuñez, Gabriel, Smith, David E. 2018. SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain-Dependent Immune Response in Mouse Bone Marrow-Derived Macrophages. In Journal of immunology (Baltimore, Md. : 1950), 201, 652-662. doi:10.4049/jimmunol.1800210. https://pubmed.ncbi.nlm.nih.gov/29784761/

5. Shen, Hong, Keep, Richard F, Hu, Yongjun, Smith, David E. 2005. PEPT2 (Slc15a2)-mediated unidirectional transport of cefadroxil from cerebrospinal fluid into choroid plexus. In The Journal of pharmacology and experimental therapeutics, 315, 1101-8. doi:. https://pubmed.ncbi.nlm.nih.gov/16107517/

6. Parker, Joanne L, Deme, Justin C, Lichtinger, Simon M, Lea, Susan M, Newstead, Simon. 2024. Structural basis for antibiotic transport and inhibition in PepT2. In Nature communications, 15, 8755. doi:10.1038/s41467-024-53096-6. https://pubmed.ncbi.nlm.nih.gov/39384780/