TRIM22 regulates macrophage autophagy and enhances Mycobacterium tuberculosis clearance by targeting the nuclear factor-multiplicity κB/beclin 1 pathway.

Abstract

Autophagy is a crucial host-defense mechanism against Mycobacterium tuberculosis (Mtb) infection by spanning innate and adaptive immune functions. TRIM22 is a member of tripartite motif family protein which involved in innate immunity and autophagy process. However, its role in the modulation of bacterial infection has not been investigated. Here, we demonstrated that TRIM22 is upregulated in a dose-dependent and time-dependent manner during Mtb infection of THP-1 cells. Downregulation of TRIM22 significantly decreased light chain 3 (LC3)-II protein level and the formation of LC3 puncta, while it markedly increased SQSTM1, a marker of autophagic degradation, in Mtb-infected THP-1 cells. What is more, enhanced bacterial survival was observed in TRIM22 knockdown THP-1 cells, while rapamycin abrogated this effect. In the presence of vector containing TRIM22 in THP-1 cells prior to infection, the survival of Mtb was decreased, while BafA restored this effect. Further study demonstrated that TRIM22 expression was regulated by MicroRNA-20b, and that TRIM22 regulates Mtb-infected THP-1 autophagy via the nuclear factor-κB/beclin 1 pathway. Using a nuclear factor-κB inhibitor BAY 11-7082, we found that TRIM22-induced high expression of LC3-II and the formation of LC3 was substantially attenuated, while the TRIM22-induced low expression of SQSTM1 was markedly increased in BAY 11-7082-treatment cells. In addition, the bacterial survival reduced by TRIM22 was significantly reversed by BAY 11-7082. Overall, these results suggest that TRIM22-augmented autophagy prevents intracellular Mtb to evade autophagic clearance, thereby inhibiting the persistence of Mtb infections.