BAG6, also known as BCL2-associated athanogene 6, BAT3 or Scythe, is a multifunctional protein involved in protein quality control. It participates in diverse physiological and pathological processes, including apoptosis, antigen presentation, T-cell response, and is essential for the quality control of aggregation-prone polypeptide biogenesis. It forms part of a complex that determines the fate of newly synthesized client proteins for membrane insertion, ubiquitin-mediated degradation and/or aggregate formation [3,4].

In influenza A virus infection, overexpression of BAG6 reduces viral protein expression and virus titers, while deletion of BAG6 significantly enhances virus replication. BAG6-knockdown mice develop more severe clinical symptoms and higher viral loads, suggesting it restricts IAV replication by inhibiting viral RNA-dependent RNA polymerase activity, promoting ubiquitination and degradation of viral polymerase subunit PB2, and perturbing RdRp complex assembly [1]. In pancreatic cancer, Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerate tumor growth dependent on EV release. Mechanistically, it is due to mast cell activation via EV-associated IL33 [2].

In conclusion, BAG6 plays essential roles in multiple biological processes and disease conditions. Its study using gene-knockout models, like in IAV-infected mice and pancreatic cancer mouse models, reveals its significance in antiviral defense and cancer progression. These findings highlight its potential as a target for antiviral drug development and in understanding pancreatic cancer mechanisms.