TRIM22 promotes K48-linked ubiquitination of LDHA, leading to the inhibition of HBV replication

Abstract

Hepatitis B virus (HBV) infection and its related liver diseases remain a major worldwide public health problem, its mechanism hasn't fully clarified. While our previous work identified TRIM22 as an interferon-stimulated gene that suppresses HBV replication via innate immune pathways, its role as an E3 ubiquitin ligase remains unclear. Here, using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), we identified lactate dehydrogenase A (LDHA) as a TRIM22-interacting protein. Subsequent experiments verified that TRIM22 binds LDHA through its coiled-coil domain and promoting K48-linked ubiquitination and proteasomal degradation of LDHA. This degradation reduces lactate production and enhances activation of the Retinoic-acid-inducible gene I (RIG-I)-Mitochondrial antiviral signaling protein (MAVS) pathway. Clinical analysis of 122 chronic hepatitis B patients revealed a positive correlation between serum LDH levels and both HBV viral load and liver injury markers. Transcriptomic and functional studies demonstrated that LDHA overexpression promotes HBV replication by suppressing the RIG-I-MAVS pathway, potentially through downregulation of C-C motif chemokine ligand 3 like 1 (CCL3L1) and C-C motif chemokine ligand 24 (CCL24). Furthermore, TRIM22 was found to negatively regulate glycolysis and lactate transport in CHB patient liver tissues. Our findings define a novel TRIM22-mediated antiviral mechanism, providing a potential foundation for new therapeutic strategies against HBV.