Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Guigen Zhang, Baca Chan, Naira Samarina, Bizunesh Abere, Magdalena Weidner-Glunde, Anna Buch, Andreas Pich, Melanie M Brinkmann, Thomas F Schulz

Research output: Contribution to journalArticlepeer-review

103 Citations (Scopus)

Abstract

The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.

Original languageEnglish
Pages (from-to)E1034-E1043
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number8
DOIs
Publication statusPublished - 23 Feb 2016
Externally publishedYes

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