Norovirus co-opts NINJ1 for selective protein secretion
Plasma membrane rupture by Ninjurin-1 (NINJ1) executes programmed cell death, releasing large cellular damage-associated molecular patterns (DAMPs). However, the regulation and selectivity of NINJ1-mediated DAMP release remain unexplored. Here, we uncover that murine norovirus (MNoV) strategically co-opts NINJ1 to selectively release the intracellular viral protein NS1, while NINJ1-mediated plasma membrane rupture simultaneously bulk-releases various cellular DAMPs. Host caspase-3 cleaves the precursor NS1/2, leading to NS1 secretion via an unconventional pathway. An unbiased CRISPR screen identifies NINJ1 as an essential factor for NS1 secretion. During infection, NINJ1 is recruited to the viral replication site, where it oligomerizes and forms speckled bodies, directly interacting with NS1. Subsequent mutagenesis studies identify critical amino acid residues of NS1 necessary for its interaction with NINJ1 and selective secretion. Genetic ablation or pharmaceutical inhibition of caspase-3 inhibits oral MNoV infection in mice. This study underscores the co-option of NINJ1 for controlled release of an intracellular viral protein.
Authors
- Joselynn Wallace (ORCID: https://orcid.org/0000-0001-8842-4921)
- Skylar A. Loeb (ORCID: https://orcid.org/0000-0003-0213-5163)
- Wandy L. Beatty (ORCID: https://orcid.org/0000-0003-0715-7361)
- A. M. Jamieson (ORCID: https://orcid.org/0000-0002-5781-9231)
- Madison S. Strine (ORCID: https://orcid.org/0000-0001-8572-1314)
- Seokoh Moon (ORCID: https://orcid.org/0000-0002-2433-5759)
- Peng Cao (ORCID: https://orcid.org/0000-0002-2044-3074)
- Mia Madel Alfajaro (ORCID: https://orcid.org/0000-0002-6402-2730)
- Timothy J. Nice (ORCID: https://orcid.org/0000-0002-4471-7666)
- Anthony Orvedahl (ORCID: https://orcid.org/0000-0002-2481-9200)
- Tiffany A. Reese (ORCID: https://orcid.org/0000-0003-2325-6546)
- Jaewon Song (ORCID: https://orcid.org/0000-0002-9387-1942)
- Craig B. Wilen (ORCID: https://orcid.org/0000-0003-2495-9403)
- Robert C. Orchard (ORCID: https://orcid.org/0000-0001-8216-4946)
- Li Zhang (ORCID: https://orcid.org/0000-0003-4803-3891)
- Sanghyun Lee (ORCID: https://orcid.org/0000-0002-0736-1648)
- Guoxun Wang (ORCID: https://orcid.org/0000-0002-8033-5980)
- Bridget A. Robinson (ORCID: https://orcid.org/0000-0002-3332-9510)
- Anne Fang (ORCID: https://orcid.org/0009-0004-4493-1779)
- Newsha Gheshm (ORCID: https://orcid.org/0009-0007-8899-0975)
Institutions
- Oregon Health & Science University (US)
- Washington University in St. Louis (US)
- Brown University (US)
- Yale University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1126/sciadv.adu7985
- Citations
- 5
- Primary Topic
- Viral gastroenteritis research and epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 6.98