TRA2A negatively regulates HIV-1-induced macrophage pyroptosis by mediating TXNIP expression in an m6A-dependent manner.

Abstract

Human Immunodeficiency Virus (HIV) infection remains a global health challenge, with the roles of N6-methyladenosine (m6A) RNA modification and Transformer 2 Alpha Homolog (TRA2A) in viral regulation yet to be fully elucidated; this study aimed to investigate how TRA2A-mediated m6A modification of Thioredoxin Interacting Protein (TXNIP) regulates macrophage pyroptosis during HIV-1 infection. Lentiviral-mediated knockdown and overexpression of TRA2A were employed to evaluate its effects on TXNIP expression, m6A modifications, and HIV-1 replication, while pyroptosis and inflammatory responses were assessed through LDH release assays, cytokine measurements, and analysis of the NLRP3/Caspase-1/GSDMD signaling pathway. Results showed significant downregulation of TRA2A in macrophages from HIV-1 patients, and TRA2A knockdown promoted viral replication while activating NLRP3/Caspase-1/GSDMD-mediated pyroptosis; mechanistically, TRA2A recognized m6A sites on TXNIP mRNA to reduce its stability, thereby inhibiting inflammasome activation, with these effects reversed by TRA2A overexpression or TXNIP/pyroptosis inhibitors, confirming TRA2A's critical role in balancing antiviral defense and inflammation control. Collectively, TRA2A functions as an m6A regulator to balance antiviral defense and inflammation via the TXNIP-mediated NLRP3 pathway, establishing a novel regulatory axis and highlighting TRA2A as a potential dual-target therapeutic candidate.