Norovirus co-opts NINJ1 for selective protein secretion.

Area of Science:

• Cell Biology
• Virology
• Immunology

Background:

• Plasma membrane rupture executed by Ninjurin-1 (NINJ1) mediates programmed cell death and releases damage-associated molecular patterns (DAMPs).
• The regulation and selectivity of NINJ1-mediated DAMP release are not well understood.
• Murine norovirus (MNoV) is a significant pathogen requiring investigation into its replication and release mechanisms.

Purpose of the Study:

• To investigate the regulation and selectivity of NINJ1-mediated plasma membrane rupture.
• To determine how MNoV interacts with NINJ1 during infection.
• To elucidate the mechanism of selective release of the viral NS1 protein.

Main Methods:

• CRISPR screening to identify host factors essential for MNoV NS1 secretion.
• Mutagenesis studies to identify critical residues in NS1 for NINJ1 interaction.
• In vivo studies involving genetic ablation and pharmaceutical inhibition of caspase-3 in MNoV-infected mice.

Main Results:

• MNoV co-opts NINJ1 to selectively release the intracellular viral protein NS1.
• NINJ1 forms speckled bodies at the viral replication site and interacts directly with NS1.
• Caspase-3 cleavage of NS1/2 precursor is essential for NS1 secretion via an unconventional pathway.
• Inhibition of caspase-3 effectively reduces oral MNoV infection in mice.

Conclusions:

• NINJ1 plays a critical role in the selective release of intracellular viral proteins.
• MNoV strategically utilizes NINJ1 to control the release of its NS1 protein.
• Targeting caspase-3 presents a potential therapeutic strategy against MNoV infection.