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

Author:

Zhang Xiaolin1,Lan Qingping1,Zhang Mingyu1,Wang Fan1,Shi Keyi1,Li Xiaojuan2,Kuang Ersheng13

Affiliation:

1. Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China

2. College of Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, Hubei 430061, China

3. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, Guangdong 510080, China

Abstract

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

Funder

MOST | National Natural Science Foundation of China

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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