KAT2A affects the inflammatory progression of lupus nephritis through multilevel regulation of cGAS.

Lysine acetyltransferase 2A (KAT2A) has been reported to modulate gene expression through acetylation on specific histone lysines. Previous research has shown that continuous inflammation promotes lupus nephritis renal damage. Our previous study has shown that KAT2A to exerts its pro-inflammatory role on this process by regulating the cyclic GMP-AMP synthase (cGAS) in immune cells. However, the underlying mechanism that KAT2A regulates cGAS expression and activation is still obscure and worth to be elucidated. Immunofluorescence was conducted to localize KAT2A primarily in the renal tubular interstitial regions of lupus nephritis (LN) tissues. Dual luciferase reporter assays and ChIP-qPCR were performed to investigate KAT2A's regulatory effects on the cGAS promoter. Additionally, we assessed the acetylation of specific lysine residues (K171, K279, and K439) on the cGAS peptide by CoIP and western blot and evaluated their impact on cGAS function. ChIP-seq was also used to localize KAT2A on severl other genes besides cGAS. Our in vitro studies demonstrated that KAT2A negatively regulates the cGAS promoter within a specific region and acetylates the K279 residue on cGAS peptide, which in turn negatively affects cGAS function. However, in vivo studies using the MRL/lpr lupus mouse model revealed that the KAT2A inhibitor MB-3 had a protective effect, significantly improving proteinuria and survival time. Given the differences between in vitro and in vivo environments, it is possible that KAT2A regulates additional molecules and signaling pathways besides cGAS. ChIP-seq analysis suggested that KAT2A may also bind to the promoter of three prime repair exonuclease 2 (TREX2), which could indirectly enhance cGAS expression. In summary, our research indicates that KAT2A negatively regulates cGAS expression and function at both transcriptional and post-translational levels in vitro. However, KAT2A exhibits a pro-inflammatory effect in a lupus mouse model, possibly due to its regulation of molecules other than cGAS. KEY MESSAGES: Lysine acetyltransferase 2A (KAT2A) negatively affects cGAS expression and function in vitro; KAT2A negatively regulates the cGAS promoter within a specific region and acetylates the K279 residue on cGAS peptide; ChIP-seq analysis suggested that KAT2A may also bind to the promoter of three prime repair exonuclease 2 (TREX2); KAT2A inhibitor MB-3 had a protective effect in MRL/lpr lupus mouse model, significantly improving proteinuria and survival time.