ZDHHC14 and APT2 regulate the palmitoylation of HSV-2 gB

Yajie Chen; Guangfu Yu; Shan Gao; Leiliang Zhang

doi:10.1016/j.virol.2025.110614

ZDHHC14 and APT2 regulate the palmitoylation of HSV-2 gB

Virology. 2025 Jun 25:610:110614. doi: 10.1016/j.virol.2025.110614. Online ahead of print.

Authors

Yajie Chen¹, Guangfu Yu², Shan Gao³, Leiliang Zhang⁴

Affiliations

¹ Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China; Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
² Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address: gfyu@sdfmu.edu.cn.
³ Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China; Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address: gaoshansdjn@163.com.
⁴ Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China; Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address: armzhang@hotmail.com.

PMID: 40582294
DOI: 10.1016/j.virol.2025.110614

Abstract

Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted pathogen known for causing genital herpes. Glycoprotein B (gB) of HSV-2 plays a crucial role in viral entry and infection. However, its post-translational modifications are not well understood. This study investigated the palmitoylation of HSV-2 gB, identifying cysteine residue 8 (C8) as a critical palmitoylation site. Using an acyl-biotin exchange assay, we confirmed that gB was indeed palmitoylated, and treatment with 2-bromopalmitate significantly reduced this modification. Further analysis revealed that ZDHHC14 interacted with gB and facilitated its palmitoylation. We also identified APT2 as a negative regulator of gB palmitoylation. Importantly, palmitoylation enhanced gB's localization to the plasma membrane, whereas the C8S mutation substantially impaired this localization. Functionally, palmitoylation of gB enhanced the infective efficiency of HSV-2 pseudotyped particles (pp) and live viruses, while both palmitoyltransferase and APT2 inhibition affected the entry efficiency of HSV-2pp. Our findings demonstrate that the palmitoylation of gB is crucial for its localization to the membrane and for facilitating efficient HSV-2 infection, highlighting palmitoylation as a promising target for antiviral interventions and providing new insights into the pathogenesis of HSV-2.

Keywords: APT2; HSV-2; Palmitoylation; ZDHHC14; gB.