Nucleotide-binding domain and
leucine-rich repeat-containing
protein 3 (NLRP3)
inflammasome-mediated
interleukin-1 beta (IL-1β) production is one of the crucial responses in innate immunity upon
infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular
proteins. Among host
proteins involved, we identified tripartite motif-containing
protein 25 (TRIM25) as a positive regulator of porcine NLRP3
inflammasome-mediated IL-1β production. TRIM25 achieved this function by enhancing the
pro-caspase-1 interaction with apoptosis-associated speck-like
protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the
E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural
protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between
pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1β signaling, while it is repressed by IAV NS1
protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.