Talaromyces marneffei suppresses human macrophages inflammatory by producing the truncated protein NCOR2-013 via TUT1-regulated alternative splicing

Abstract

ABSTRACTTalaromyces marneffei (T. marneffei) immune-escaping is an important factor for high mortality of talaromycosis. It is currently known that T. marneffei performs these functions through a variety of strategies, however, the role of alternative splicing (AS) in this process is poorly understood. Here we depicted the AS landscape in the macrophage upon T. marneffei infection via high-throughput RNA sequencing. Moreover, we identified a truncated protein of NCOR2/SMRT, namedly NCOR2-013, was significantly upregulated upon T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1/TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Also, we identified TUT1 as the AS regulator that involved in facilitating T. marneffei immune evasion via regulation of NCOR2-013 production. Collectively, the findings indicate that T. marneffei escapes macrophages killing through the TUT1-mediated the alternative splicing of NCOR2-013, which providing a new insight into the molecular mechanisms of T. marneffei immune evasion, and a potential targets for talaromycosis therapy.