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Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization

Yanxia Huang1,2,3, Qinyu Peng1,2, Xu Tian1,2

  • 1Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Nature Communications
|January 4, 2024
PubMed

Insights

Nuclear protein SUN2 is essential for flavivirus replication, including Zika virus (ZIKV) and dengue virus (DENV). SUN2 facilitates viral RNA synthesis by linking the cytoskeleton to the nucleus, impacting viral infection.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Flaviviruses, including Zika virus (ZIKV), dengue virus (DENV), and Japanese encephalitis virus (JEV), extensively utilize the host cell cytoskeleton during infection.
  • The precise mechanisms by which flaviviruses interact with and manipulate the cytoskeleton, particularly connections to the nucleus, remain incompletely understood.

Purpose of the Study:

  • To investigate the role of nuclear membrane proteins, specifically SUN1 and SUN2, in flavivirus replication.
  • To elucidate the molecular mechanisms by which SUN2 influences viral RNA synthesis and cytoskeleton rearrangement during flavivirus infection.

Main Methods:

  • CRISPR/Cas9-mediated gene knockout of SUN1 and SUN2 in host cells.
  • Assessing viral replication levels for ZIKV, DENV, JEV, and non-flaviviridae RNA viruses.
  • Investigating protein-protein interactions using dominant-negative Nesprin constructs.
  • Evaluating viral replication and neuropathology in a neonatal mouse model.

Main Results:

  • SUN2 knockout significantly reduced ZIKV, DENV, and JEV replication, while SUN1 knockout had no significant effect.
  • SUN2's proviral activity required all three of its functional regions.
  • SUN2 facilitated cytoskeleton rearrangement and replication organelle formation, promoting viral RNA synthesis.
  • SUN2 was essential for the interaction between cytoskeletal actin and ZIKV nonstructural protein 1 (NS1).
  • Disruption of SUN2-cytoskeleton connections via Nesprins reduced viral replication.
  • SUN2 knockout dramatically reduced in vivo ZIKV replication and neuropathology in neonatal mice.

Conclusions:

  • SUN2 plays a critical, proviral role in flavivirus replication by coordinating the recruitment of cytoskeletal proteins.
  • The nuclear membrane protein SUN2 acts as a crucial link between the cytoskeleton and nucleoskeleton, facilitating flavivirus infection.
  • SUN2 and Nesprins are key mediators in the host's response to flavivirus infection, highlighting a novel therapeutic target.

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