DRAM1 promotes the targeting of mycobacteria to selective autophagy

Abstract

Autophagy provides an important defense mechanism against intracellular bacteria, such as Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis disease (TB). We recently reported that pathogen recognition and antibacterial autophagy are connected by the induction of the DNA damage-regulated autophagy modulator DRAM1 via the toll-like receptor (TLR)-MYD88-NFKB innate immunity signaling pathway. Having shown that DRAM1 colocalizes with Mtb in human macrophages, we took advantage of a zebrafish model for TB to investigate the function of DRAM1 in autophagic host defense in vivo. We found that DRAM1 protects the zebrafish host from infection with Mycobacterium marinum (Mm), a close relative of Mtb. Overexpression of DRAM1 increases autophagosome formation and promotes autophagic flux by a mechanism dependent on the cytosolic DNA sensor TMEM173/STING and the ubiquitin receptor SQSTM1/p62. Here we summarize and discuss the implications of these findings.

Keywords: DRAM1; LC3; MYD88; Mycobacterium marinum; Mycobacterium tuberculosis; NFκB; STING; macrophages; p62; zebrafish.

Figure 1.

Model for DRAM1 function in host defense against mycobacteria. TLR recognition of mycobacterial ligands leads to formation of the myddosome (a complex consisting of MYD88-IRAKs-TRAF6), which induces DRAM1 transcription via nuclear translocation of NFKB. Mycobacteria replicate in phagosomes and eventually use RD1-dependent virulence factors to partly escape into the cytoplasm. Release of mycobacterial DNA is thought to trigger activation of TMEM173, ubiquitination of mycobacteria, and recognition by the selective autophagy receptor SQSTM1. DRAM1 protein, localizing on lysosomes and autophagosomes, stimulates formation of autophagosomes and promotes maturation of mycobacteria-containing compartments by facilitating their fusion with lysosomes and autophagosomes that may deliver neo-antimicrobial peptides derived from ubiquitinated cytosolic proteins. DRAM1, DNA-damage regulated autophagy modulator 1; TLR, toll-like receptor; MYD88, myeloid differentiation primary response 88, IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF receptor-associated factor 6, E3 ubiquitin protein ligase; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; SQSTM1/p62, sequestosome 1; TMEM173/STING, transmembrane protein 173.