Sit1, also known as Sodium-dependent Imino Transporter 1 (SLC6A20), is a crucial transporter. It is involved in the transport of amino acids, especially proline, and plays a role in multiple biological processes. In the SLC6 family, it contributes to the regulation of amino acid homeostasis, which is essential for normal cellular function. Understanding its function can be significantly enhanced through genetic models like KO/CKO mouse models [1,3,5].

A pharmacophore-guided screen identified tiagabine as a potent non-competitive inhibitor of SIT1. The cryo-EM structure of ACE2-SIT1 bound with tiagabine showed that the inhibitor causes the transporter to adopt an inward-open conformation, blocking the intracellular gate, providing the first structural insight into SIT1 inhibition [1]. In Aspergillus fumigatus, inactivation of Sit1, an importer for ferrichrome-type siderophores, renders the fungus resistant to the antifungal VL-2397, indicating that Sit1-mediated uptake is essential for VL-2397 susceptibility [2].

Studies also suggest an association of SLC6A20 (Sit1) with the risk and severity of COVID-19, and its interaction with the ACE2 receptor for SARS-CoV-2. Additionally, SIT1 may be a novel regulator of glycine levels, which has beneficial effects against the pro-inflammatory cytokine secretion induced by SARS-CoV-2 infection [3].

In systemic lupus erythematosus (SLE) patients, SIT1 expression is altered in T cells, accompanied by an augmented secretion of cytotoxic molecules, which may contribute to the pathogenesis of SLE and enhance its diagnostic potential [4].

In cutaneous melanoma, the high expression of SIT1 was closely related to improved survival, and a 13-gene signature based on SIT1-associated immunomodulators served as an independent prognostic factor for melanoma patients [6].

In rice, the receptor-like kinase SIT1 acts as a sensor in roots, relaying salt stress signals to enhance salt sensitivity, and is regulated by B'κ-PP2A [7].

In A. fumigatus, Sit1 and Sit2 have overlapping and unique substrate specificities for ferrichrome -, ferrioxamine-and coprogen-type siderophores [8]. Also, SIT1 is not expressed in the small intestine of human newborns, similar to the situation in the proximal kidney tubule [9].

In conclusion, Sit1 has diverse functions, including amino acid transport, involvement in fungal susceptibility to antifungals, potential roles in COVID-19, SLE, cutaneous melanoma, salt stress response in rice, and siderophore utilization in fungi. Its absence in the small intestine of human newborns is also an important finding. Research on Sit1 using genetic models has provided valuable insights into these biological processes and disease-related conditions, contributing to a better understanding of relevant physiological and pathological mechanisms.

References:

1. Bröer, Angelika, Hu, Ziwei, Kukułowicz, Jędrzej, Yan, Renhong, Bröer, Stefan. 2024. Cryo-EM structure of ACE2-SIT1 in complex with tiagabine. In The Journal of biological chemistry, 300, 107687. doi:10.1016/j.jbc.2024.107687. https://pubmed.ncbi.nlm.nih.gov/39159813/

2. Dietl, Anna-Maria, Misslinger, Matthias, Aguiar, Mario M, Smith, Larry R, Haas, Hubertus. 2019. The Siderophore Transporter Sit1 Determines Susceptibility to the Antifungal VL-2397. In Antimicrobial agents and chemotherapy, 63, . doi:10.1128/AAC.00807-19. https://pubmed.ncbi.nlm.nih.gov/31405865/

3. Semiz, Sabina. 2021. SIT1 transporter as a potential novel target in treatment of COVID-19. In Biomolecular concepts, 12, 156-163. doi:10.1515/bmc-2021-0017. https://pubmed.ncbi.nlm.nih.gov/34969185/

4. Hasimu, Ainizati, Bahabayi, Ayibaota, Xiong, Ziqi, Yuan, Zihang, Liu, Chen. 2024. SIT1 identifies circulating hypoactive T cells with elevated cytotoxic molecule secretion in systemic lupus erythematosus patients. In Immunologic research, 72, 754-765. doi:10.1007/s12026-024-09481-w. https://pubmed.ncbi.nlm.nih.gov/38691318/

5. Li, Huanyu Z, Pike, Ashley C W, Lotsaris, Irina, Carpenter, Elisabeth P, Sauer, David B. 2024. Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2. In Nature communications, 15, 5503. doi:10.1038/s41467-024-48921-x. https://pubmed.ncbi.nlm.nih.gov/38951531/

6. Jia, Ming, Liu, Chengfei, Liu, Yuean, Jiang, Yuhua, Sun, Xifeng. 2022. Discovery and Validation of a SIT1-Related Prognostic Signature Associated with Immune Infiltration in Cutaneous Melanoma. In Journal of personalized medicine, 13, . doi:10.3390/jpm13010013. https://pubmed.ncbi.nlm.nih.gov/36675674/

7. Zhao, Ji-Long, Zhang, Li-Qing, Liu, Ning, Sun, Ying, Zhang, Sheng-Wei. 2019. Mutual Regulation of Receptor-Like Kinase SIT1 and B'κ-PP2A Shapes the Early Response of Rice to Salt Stress. In The Plant cell, 31, 2131-2151. doi:10.1105/tpc.18.00706. https://pubmed.ncbi.nlm.nih.gov/31221736/

8. Aguiar, Mario, Orasch, Thomas, Misslinger, Matthias, Gsaller, Fabio, Haas, Hubertus. 2021. The Siderophore Transporters Sit1 and Sit2 Are Essential for Utilization of Ferrichrome-, Ferrioxamine- and Coprogen-Type Siderophores in Aspergillus fumigatus. In Journal of fungi (Basel, Switzerland), 7, . doi:10.3390/jof7090768. https://pubmed.ncbi.nlm.nih.gov/34575806/

9. Meier, C, Camargo, S M, Hunziker, S, Verrey, F, Vuille-Dit-Bille, R N. 2018. Intestinal IMINO transporter SIT1 is not expressed in human newborns. In American journal of physiology. Gastrointestinal and liver physiology, 315, G887-G895. doi:10.1152/ajpgi.00318.2017. https://pubmed.ncbi.nlm.nih.gov/30160974/