SUN2 Induces Cytoskeleton Rearrangement via Nesprins and NS1 to Promote Flavivirus Replication

Flaviviruses are positive-sense RNA viruses, generally arthropod transmitted, that can cause serious disease in humans. Viral infection leads to ER membrane remodeling, replication organelle (RO) formation, and cytoskeletal reorganization as essential processes for viral replication. The cytoskeleton and nucleoskeleton are linked by SUN proteins on the inner nuclear membrane and Nesprins on the outer nuclear membrane, and SUN proteins are known to be important for HIV-1 and herpes simplex virus infection. However, little is known about their role in the life cycles of cytoplasmic-replicating, RNA viruses.

A recent study by Huang et al. sought to explore the functions of two widely-expressed SUN proteins, SUN1 and SUN2, in flavivirus infection (1). The researchers discovered that CRISPR/Cas9-mediated knockout of SUN2, but not SUN1, reduced the replication of multiple flaviviruses including DENV, ZIKV, and JEV, with no impact on other non-flaviviridae RNA viruses. Deletion analysis of SUN2 showed that the full-length protein is required to promote ZIKV replication. A series of mechanistic experiments demonstrated that SUN2 is crucial for ER remodeling, RO formation, and cytoskeletal reorganization. The team then revealed that SUN2 is essential for an interaction between ZIKV NS1 and actin via Nesprin-1 and -2. Intriguingly, ZIKV-infected SUN2 knockout mice displayed longer survival times and less paralysis and microcephaly than wild-type mice, and viral loads that were 2-3 logs lower. This report by Huang et al. presents a new perspective on key cellular factors affecting flavivirus infection, and offers a novel therapeutic target for potential antiviral intervention.

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