Direct cleavage of caspase-8 by herpes simplex virus 1 tegument protein US11

• Published in: Scientific reports Vol. 12; no. 1; p. 12317
• Main Authors: Musarra-Pizzo, Maria, Pennisi, Rosamaria, Lombardo, Daniele, Velletri, Tania, Sciortino, Maria Teresa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-07-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326; 631/326/596; Apoptosis; Autophagy; Caspase-8; Cell death; Herpes simplex; Herpes viruses; Humanities and Social Sciences; Kinases; multidisciplinary; Replication; Science; Science (multidisciplinary); Staurosporine; Tegument; Viral infections
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-15942-9

The HSV-1 tegument protein Us11 counteracts the antiviral defense mechanisms by precluding the host protein shutoff. Previous works demonstrated that Us11 prevents heat-and staurosporine-induced apoptosis and inhibits autophagy. Therefore, in the present study, we investigated the hypothesis that HSV-1, through Us11, could recruit caspase-8, a key enzyme regulating programmed cell death. We first show that HSV-1 promotes the accumulation of caspase-8-p18 active fragments in both semi permissive THP-1 cells and fully permissive HEp-2 cells to HSV-1 replication. Using a recombinant virus R3630 (ΔUs11/ΔUs12) and a plasmid encoding Us11-recombinant protein we have proven that Us11 promotes p18 accumulation, which does not trigger the apoptotic signaling. Additional, in an in vitro model, we demonstrated that Us11-recombinant protein induces caspase-8-p18 cleavage by physically interacting with the caspase-8 recombinant protein. Finally, we found that, during HSV-1 replication, activated-caspase-8 cleaves Atg3 protein to potentially block autophagy and support its replication.