UC Riverside

Influenza A Viruses (IAV’s) pose a significant threat to public health. On average, Influenza infections account for 25,000 deaths and 250,000 hospitalizations every year in the United States. Despite having been discovered in the 1930’s, and despite decades of study influenza viruses continue to cause significant morbidity and mortality. Furthermore, with the emergence of Highly Pathogenic Avian Influenza Viruses (HPAIV) in humans, IAV’s pose a greater threat than ever before. The innate immune response is critical to controlling these viral infections, but despite over half a century passing since the discovery of the first innate immune proteins, the full scope of innate immunity has yet to be elucidated. The Interferon-Induced Transmembrane (IFITM) family of proteins has been shown to strongly restrict a broad range of viruses, including IAV5,6,7. However, the exact mechanism of this inhibition as well as the mechanism of IFITM regulation and metabolism is poorly understood. Secretory Membrane Protein 3(SCAMP3) was first identified in 1997 and has since been implicated in EGFR recycling and Salmonella pathogenesis. Here we demonstrate a new function of SCAMP3 in the innate immune response. We show that SCAMP3 can function to stabilize IFITM3 by decreasing its lysosomal degradation. We show that SCAMP3 can alter the trafficking of IFITM, resulting in the protein being recycled from early endosomes back to the Golgi apparatus. Upon SCAMP3 depletion, this recycling is ablated and IFITM3 undergoes increased lysosomal degradation. We also show that SCAMP3 can directly restrict Influenza A Viruses. We show that SCAMP3 and interfere with cleavage of Highly Pathogenic Avian Influenza (HPAIV) Hemagglutinin (HA) cleavage, resulting in viruses that are deficient in their ability to enter target cells. We also show that SCAMP3 expression, phosphorylation and localization is altered upon viral infection or stimulation with various innate immune proteins, suggesting that SCAMP3 is an innate immune effector. This research deepens our understanding of the innate immune response and presents a potential therapeutic strategy for treatment or prophylaxis of viral disease.