Circular RNA TRAPPC6B inhibits intracellular Mycobacterium tuberculosis growth while inducing autophagy in macrophages by targeting microRNA-874-3p

Objectives. Genetic and epigenetic mechanisms regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection. Methods. The present study assessed circular RNA TRAPPC6B (circTRAPPC6B) for antimicrobial immune functions and defined mechanisms wherein circTRAPPC6B regulates Mtb growth, autophagy and microRNA in macrophages. Results. The Mtb infection of monocytes/macrophages resulted in a significantly decreased level of circTRAPPC6B that inhibited intracellular Mtb growth in macrophages. Conversely, circTRAPPC6B expression enhanced autophagy or autophagy-associated protein LC3-II production in Mtb-infected macrophages. circTRAPPC6B-enhanced autophagy aggregation or sequestration was also observed in fluorescence in situ hybridisation (FISH) analysis and confocal imaging. Mechanistically, circTRAPPC6B targets an inhibiting element miR-874-3p, as shown by bioinformatics, dual-luciferase reporter gene analysis and pull-down assay, respectively. Notably, miR-874-3p prohibited autophagy via suppressing autophagy protein ATG16L1 by binding to its 3'-untranslated region (UTR) in Mtb-infected macrophages and thus promoting intracellular Mtb growth. Concurrently, circTRAPPC6B enhanced autophagy in Mtbinfected macrophages by blocking the ability of miR-874-3p to inhibit ATG16L1. Thus, circTRAPPC6B antagonises the ability of miR-874-3p to suppress ATG16L1 expression and activate and enhance autophagy sequestration to restrict Mtb growth in macrophages. Conclusion. The current findings suggested that both circTRAPPC6B and miR-874-3p mechanisms can be explored as potential therapeutics against Mtb infection.

Automated summary

Genetic and epigenetic mechanisms regulate antimicrobial immunity against Mycobacterium tuberculosis (Mtb) infection. The circular RNA TRAPPC6B (circTRAPPC6B) enhances autophagy and sequestration to restrict Mtb growth by targeting miR-874-3p and inhibiting its ability to suppress ATG16L1 in Mtb-infected macrophages. Both circTRAPPC6B and miR-874-3p mechanisms have the potential to be explored as therapeutics against Mtb infection.