STT3A-mediated mega protein complex assembly during dengue and Zika virus infection

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• Flavivirus replication in mammalian cells depends on the host oligosaccharyltransferase (OST) complex.
• The OST complex's enzymatic N-glycosylation activity is not essential for flavivirus infection, indicating a non-canonical role.
• The precise mechanism of OST involvement in flavivirus infection remains unclear.

Purpose of the Study:

• To elucidate the specific role of the OST complex, particularly the STT3A sub-complex, in flavivirus replication.
• To identify host factors and viral interactions involving the OST complex during infection.
• To discover small molecules that can inhibit flavivirus infection by targeting the OST complex.

Main Methods:

• Investigated the requirement of the STT3A sub-complex (STT3A and DC2) for dengue virus (DENV) and Zika virus (ZIKV) infection.
• Analyzed the STT3A sub-complex's role in nucleating large protein complex assembly during DENV infection.
• Utilized a small-molecule compound (NSC-323241) to disrupt STT3A-mediated complex formation and assess its impact on viral infection.

Main Results:

• The STT3A sub-complex of OST is essential for DENV and ZIKV infection.
• STT3A functions as a scaffold, nucleating a mega protein complex involving OST subunits, translocon proteins, and viral nonstructural proteins during DENV infection.
• The integrity of this mega protein complex is vital for supporting flavivirus replication.
• The compound NSC-323241 effectively disrupts STT3A-mediated complex assembly and inhibits DENV and ZIKV infection.

Conclusions:

• The STT3A sub-complex plays a critical scaffolding role in flavivirus infection, independent of its enzymatic N-glycosylation activity.
• Disruption of STT3A-mediated mega protein complex assembly represents a potential therapeutic strategy against flaviviruses like DENV and ZIKV.
• This study provides a comprehensive molecular understanding of the OST complex's involvement in flavivirus replication.