Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

Abstract

Viruses acquire host genes via horizontal gene transfer and can express them to manipulate host biology during infections. Some viral and host homologs retain sequence identity, but evolutionary divergence can obscure host origins. We used structural modeling to compare vaccinia virus proteins with metazoan proteomes. We identified vaccinia A47L as a homolog of gasdermins, the executioners of pyroptosis. An X-ray crystal structure of A47 confirmed this homology and cell-based assays revealed that A47 inhibits pyroptosis. We also identified vaccinia C1L as the product of a cryptic gene fusion event coupling a Bcl-2 related fold with a pyrin domain. C1 associates with components of the inflammasome, a cytosolic innate immune sensor involved in pyroptosis, yet paradoxically enhances inflammasome activity, suggesting a benefit to poxvirus replication in some circumstances. Our findings demonstrate the potential of structural homology screens to reveal genes that viruses capture from hosts and repurpose to benefit viral fitness.

Birth of new protein folds and functions in the virome

“…First, we found that a set of proteins encoded by poxviruses are structurally similar to the auto-inhibitory domain of mammalian gasdermins (Fig. 3D) 32 . Similarly, several poxvirus proteins are structurally homologous to the human galactosyltransferase COLGALT1, thought to enable virus binding to surface glycosaminoglycans during viral entry (Fig.…”

The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity

“…Protein B14 blocks NF-κB activation by binding to IKKβ and thereby prevents phosphorylation of IκBα [ 15 ]. Protein C1 is not anti-apoptotic [ 16 ] but promotes inflammasome activation [ 17 ]. Protein C6 is a multifunctional IFN antagonist that inhibits IRF3 activation in 2 ways.…”