Quo vadis? Interferon-inducible GTPases go to their target membranes via the LC3-conjugation system of autophagy

Many intracellular pathogens survive and replicate within vacuole-like structures in the cytoplasm. It has been unclear how the host immune system controls such pathogen-containing vacuoles. Interferon-inducible GTPases are dynamin-like GTPases that target the membranes of pathogen-containing vacuoles. Upon their oligomerization on the membrane, the vacuole structure disintegrates and the pathogen gets exposed to the hostile cytoplasm. What has been obscure is how the immune system detects and directs the GTPases to these pathogen shelters. Using a common protist parasite of mice, Toxoplasma gondii, we found that the LC3 conjugation system of autophagy is necessary and sufficient for targeting the interferon-inducible GTPases to membranes. We dubbed this process Targeting by AutophaGy proteins (TAG). In canonical autophagy, the LC3 conjugation system is required to form membrane-bound autophagosomes, which encircle and deliver cytosolic materials to lysosomes for degradation. In TAG, however, the conjugation system is required to mark the membranes of pathogen-containing vacuoles with ubiquitin-like LC3 homologs, which function as molecular beacons to recruit the GTPases to their target membranes. Our data suggest that the LC3 conjugation system of autophagy plays an essential role in detecting and marking pathogen-containing vacuoles for immune effector targeting by the host immune system.