MFSD6 is an entry receptor for respiratory enterovirus D68

Xize Liu; Huili Li; Zhaoxue Li; Delong Gao; Junfeng Zhou; Fushun Ni; Qing Yu; Yuehan Huang; Yubin Tang; Ling Xue; Shijin Wang; Jiaxin Yang; Haoran Guo; Yonggang Wang; Xiao-Fang Yu; Zhenglei Yu; Wei Wei

doi:10.1016/j.chom.2024.12.015

MFSD6 is an entry receptor for respiratory enterovirus D68

Cell Host Microbe. 2024 Dec 31:S1931-3128(24)00482-7. doi: 10.1016/j.chom.2024.12.015. Online ahead of print.

Authors

Xize Liu¹, Huili Li¹, Zhaoxue Li², Delong Gao³, Junfeng Zhou⁴, Fushun Ni¹, Qing Yu⁵, Yuehan Huang¹, Yubin Tang¹, Ling Xue¹, Shijin Wang¹, Jiaxin Yang², Haoran Guo¹, Yonggang Wang⁶, Xiao-Fang Yu⁷, Zhenglei Yu³, Wei Wei⁸

Affiliations

¹ Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China; Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
² Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
³ The Key Laboratory of Bionic Engineering, Ministry of Education, Jilin University, Changchun, Jilin 1300121 China.
⁴ Department of Dermatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
⁵ Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China; Department of Pathology, Medical College, Yanbian University, Yanji, Jilin 136200, China.
⁶ Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
⁷ Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
⁸ Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China; Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin 130021, China; Institute of Translational Medicine, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address: [email protected].

PMID: 39798568
DOI: 10.1016/j.chom.2024.12.015

Abstract

Enterovirus D68 (EV-D68) is a leading non-polio enterovirus that causes severe respiratory diseases and poliomyelitis-like illness in children. Viral entry represents a potential multifaceted target for antiviral intervention; however, there are no approved inhibitors to block EV-D68. Here, we identify the functionally undescribed membrane protein major facilitator superfamily-domain-containing protein 6 (MFSD6) as an EV-D68 entry factor amenable to therapeutic intervention. Specifically, MFSD6 expression is crucial for EV-D68 replication. MFSD6 binds to EV-D68 particles and is necessary for virus attachment to cells. The second extracellular domain of the MFSD6 molecule is involved in the recognition of EV-D68. On the basis of these findings, we engineered a recombinant protein complex comprising the MFSD6 ectodomain fused to Fc (MFSD6-Fc(CH3)), which potently inhibited EV-D68 uptake. MFSD6-Fc(CH3) effectively blocked EV-D68 infection in vitro and prevented lethality in newborn mice. In conclusion, our study not only identifies MFSD6 as an EV-D68 entry factor but also reveals a potential antiviral target and therapeutic agent.

Keywords: EV-D68; MFSD6; antiviral agent; viral entry; virus receptor.