The HMGBa-HSP70-ATF4-β Axis Restricts White Spot Syndrome Virus Infection in Crayfish.

Envelope viruses are the most threatening pathogens to eukaryotes. The search for target genes against envelope viruses is particularly important. The activating transcription factors (ATFs) regulate cancer proliferation, maintain cellular redox homeostasis, extend biological longevity, and respond to viral stimuli. However, the mechanism of ATF antiviral immunity, especially envelope viruses, is rarely reported. Two ATF4 homologs (ATF4-α and ATF4-β) with a difference of one β sheet (7 amino acids) were identified in crayfish. Further studies showed that ATF4-β was activated and significantly translocated into the nucleus after envelope virus white spot syndrome virus (WSSV) infection. During WSSV infection, the host may recognize WSSV in some way (such as HMGBa recognizing WSSV by interacting with WSSV/VP28) and transmits the signal to cell, and then HMGBa, HSP70, and ATF4-β interact with each other in the cytoplasm and promote nuclear translocation of ATF4-β. ATF4-β entered the nucleus to initiate the transcription of ATF4 and ALFs. In addition, ALF1 could bind to VP28 to inhibit virus assembly in the nucleus and reinfection. This study elucidated a novel mechanism of ATF4-β in antienvelope virus immune responses, and ATF4 may be a potential target for disease prevention and control.