Eliminate Mycobacterium tuberculosis via HELZ2 and up-regulating ATG16L1 to promote macrophage autophagy

Introduction. Tuberculosis (TB) remains a major global health threat, and its control is hindered by prolonged treatment and increasing drug resistance. Helicase with zinc finger 2 (HELZ2) has recently been identified as an RNA-binding protein up-regulated after Mycobacterium tuberculosis (Mtb) infection, yet its functional contribution to host defence is not fully understood.Hypothesis/Gap Statement. Although HELZ2 expression increases following Mtb infection, the molecular mechanism by which HELZ2 regulates macrophage immunity, particularly autophagy-mediated bacterial clearance, remains unclear.Aim. This study aimed to elucidate the role and underlying mechanism of HELZ2 in macrophage-mediated elimination of Mtb, with a specific focus on its regulation of autophagy.Methodology. HELZ2 expression was quantified in the peripheral blood of TB patients and in Mtb-infected monocyte-derived macrophages. By knocking out and overexpressing genes, phagocytosis, intracellular bacterial survival and autophagy were analysed. Co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase assays were employed to identify HELZ2-interacting proteins and downstream transcriptional targets.Results. HELZ2 was significantly up-regulated in patient samples and infected macrophages. HELZ2 silencing impaired phagocytosis, reduced autophagic flux and increased intracellular Mtb survival. Mechanistically, HELZ2 bound to and stabilized the MYC proto-oncogene, bHLH transcription factor (MYC), which directly activated transcription of the autophagy-related gene ATG16L1. Overexpression of MYC or ATG16L1 restored the autophagy disorder caused by HELZ2 deficiency and enhanced bacterial clearance.Conclusion. HELZ2 enhances macrophage autophagy and promotes intracellular Mtb elimination by interacting with MYC and up-regulating ATG16L1. This newly identified HELZ2-MYC-ATG16L1 regulatory axis provides mechanistic insight into host defence and suggests a potential target for host-directed TB therapies.