Abstract
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.
Highlights
Interleukin-1 beta (IL-1β) plays a central role in mediating inflammation by recruiting immune cells and supporting the clearance of pathogens
Since the upregulation of IL-1β production by tripartite motif-containing protein 25 (TRIM25) was more significant than that by TRAF6 and this dramatic effect on IL-1β signaling by TRIM25 has not been reported, we focused on the roles of TRIM25 on nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome activation
To further confirm that TRIM25 plays a positive role on NLRP3 inflammasome-mediated IL-1β production, NLRP3 inflammasome reconstitution was performed in another setting where increasing amounts of the TRIM25-expressing plasmid were included in each condition
Summary
Interleukin-1 beta (IL-1β) plays a central role in mediating inflammation by recruiting immune cells and supporting the clearance of pathogens. For the regulation of IL-1β production, nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) functions as a limiting factor by forming the NLRP3 inflammasome with the adaptor protein, apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), and the effector molecule, pro-caspase-1. Viral proteins can either inhibit or activate the NLRP3 inflammasome (Choudhury et al, 2021). Members of tumor necrosis factor alpha (TNF-α) receptor-associated factors (TRAFs) and tripartite motif-containing proteins (TRIMs) are defined to regulate the NLRP3 inflammasome-mediated IL-1β by functioning as a key enzyme in ubiquitination/SUMOylation. TRAF3 activates the NLRP3 inflammasome by ASC ubiquitination (Guan et al, 2015; Siu et al, 2019). TRAF6 can either inhibit the NLRP3 inflammasome by ubiquitinating ASC (Chiu et al, 2016), or prime the NLRP3 inflammasome thereby activating the complex (Xing et al, 2017). Negative regulation of the NLRP3 inflammasome by TRIM24, TRIM30, and TRIM31 is demonstrated (Hu et al, 2010; Song et al, 2016; Hang et al, 2021)
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