Abstract: Kaposi sarcoma-associated herpesvirus (KSHV), a human DNA tumor virus, is the causative agent of Kaposi sarcoma and various cancers. The cytoplasmic DNA sensor cGAS, activated upon DNA binding, catalyzes dinucleotide cyclic GMP-AMP (cGAMP) synthesis and induces a potent antiviral response. Viruses, including KSHV, have evolved strategies to manipulate cGAS-DNA condensation to persist in the hosts. KSHV inhibitor of cGAS (KicGAS), encoded by ORF52, is a conserved major tegument protein of KSHV and the first reported viral inhibitor of cGAS. KicGAS exhibits high oligomerization in solution, a crucial prerequisite for its DNA-binding capacity and inhibition of cGAS. To elucidate the structural basis of this oligomerization, we solved the crystal structure of KicGAS. The structure reveals how self-oligomerization increases the valence and cooperativity of interaction with DNA. This multivalent interaction is vital for liquid condensate formation with DNA, sequestering DNA from cGAS and restricting its activation. Comparison with homologous protein structures reveals diverse oligomerization characteristics and conserved features, highlighting divergence in virus evolution. The KicGAS crystal structure not only provides mechanistic insights into KicGAS function but also identifies a potential molecular target for designing antivirals against KSHV and related viruses.

Meeting ID: 925 9548 7187
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