Mfsd6, a member of the major facilitator superfamily, is phylogenetically related to the human Solute Carrier (SLC) transporter family [3]. It has a predicted structure with 12 transmembrane segments and the classical MFS fold. Immunohistological analyses showed its specific staining in neurons of wild-type mouse brain tissue [3]. Although its exact function remains to be fully elucidated, studies suggest its involvement in processes related to energy consumption in the brain [3].

Knockout of Mfsd6 expression abrogated enterovirus D68 (EV-D68) infection in cell lines and primary cells corresponding to respiratory and neural cells. MFSD6 localized to the plasma membrane and was required for viral entry into host cells. It bound directly to EV-D68 particles through its extracellular, third loop (L3). A decoy receptor, engineered by fusing MFSD6 L3 to Fc, blocked EV-D68 infection of human primary lung epithelial cells and provided near-complete protection in a lethal mouse model of EV-D68 infection [2].

In conclusion, Mfsd6 is crucial for EV-D68 replication and acts as an entry receptor for the virus [1,2]. Its role in the brain during energy consumption further indicates its importance in normal physiological processes. The gene knockout models in the context of EV-D68 infection have revealed a potential antiviral target, highlighting the significance of Mfsd6 in both normal biology and infectious disease research.

References:

1. Liu, Xize, Li, Huili, Li, Zhaoxue, Yu, Zhenglei, Wei, Wei. 2025. MFSD6 is an entry receptor for respiratory enterovirus D68. In Cell host & microbe, 33, 267-278.e4. doi:10.1016/j.chom.2024.12.015. https://pubmed.ncbi.nlm.nih.gov/39798568/

2. Varanese, Lauren, Xu, Lily, Peters, Christine E, Chiu, Wah, Carette, Jan E. 2025. MFSD6 is an entry receptor for enterovirus D68. In Nature, , . doi:10.1038/s41586-025-08908-0. https://pubmed.ncbi.nlm.nih.gov/40132641/

3. Bagchi, Sonchita, Perland, Emelie, Hosseini, Kimia, Kheder, Sania, Fredriksson, Robert. 2020. Probable role for major facilitator superfamily domain containing 6 (MFSD6) in the brain during variable energy consumption. In The International journal of neuroscience, 130, 476-489. doi:10.1080/00207454.2019.1694020. https://pubmed.ncbi.nlm.nih.gov/31906755/