Inhibition of AIM2 inflammasome activation by SOX/ORF37 promotes lytic replication of Kaposi's sarcoma-associated herpesvirus

• DOI: 10.1073/pnas.2300204120
• Publication Date: 2023-06-26T19:09:49Z
• Authors: Xiaolin Zhang; Qingping Lan; Mingyu Zhang; Fan Wang; Keyi Shi; Xiaojuan Li; Ersheng Kuang
• Keywords: AIM2; Pyroptosis; Kaposi's sarcoma-associated herpesvirus; Lytic cycle

Inflammasomes are one kind of important innate immune defense against viral and bacterial infections. Several inflammasome-forming sensors detect molecular patterns invading pathogens then trigger inflammasome activation and/or pyroptosis in infected cells, viruses employ unique strategies to hijack or subvert activation. Infection with herpesviruses induces the diverse inflammasomes, including AIM2 IFI16 inflammasomes; however, how Kaposi's sarcoma-associated herpesvirus (KSHV) counteracts largely remains unclear. Here, we reveal that KSHV ORF37-encoded SOX protein suppresses independent its DNA exonuclease activity host mRNA turnover. interacts HIN domain through C-terminal Motif VII region disrupts AIM2:dsDNA polymerization ASC recruitment oligomerization. The Y443A F444A mutation abolishes inhibition without disrupting nuclease activity, a short peptide is capable inhibiting activation; consequently, infection SOX-null, Y443A, Bac16 recombinant results robust activation, suppressed lytic replication, increased human lymphatic endothelial cells an AIM2-dependent manner. These promote replication inhibit pyroptosis, representing mechanism for evasion during cycle.