<i>Vibrio cholerae</i> cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy
Dale Corkery, Aftab Nadeem, Kyaw Min Aung, Ahmed Hassan, Tao Liu, Ramón Cervantes-Rivera, Alf Håkon Lystad, Hui Wang, Karina Persson, Andrea Puhar, Anne Simonsen, Bernt Eric Uhlin, Sun Nyunt Wai, Yao‐Wen Wu
Abstract
Autophagy plays an essential role in the defence against many microbial pathogens as a regulator of both innate and adaptive immunity. Among some pathogens, sophisticated mechanisms have evolved that promote their ability to evade or subvert host autophagy. Here, we describe a novel mechanism of autophagy modulation mediated by the recently discovered Vibrio cholerae cytotoxin, MakA. pH-dependent endocytosis of MakA by host cells resulted in the formation of a cholesterol-rich endolysosomal membrane aggregate in the perinuclear region. Aggregate formation induced the noncanonical autophagy pathway driving unconventional LC3 lipidation on endolysosomal membranes. Subsequent sequestration of the ATG12-ATG5-ATG16L1 E3-like enzyme complex required for LC3 lipidation at the membranous aggregate resulted in an inhibition of both canonical autophagy and autophagy-related processes including the unconventional secretion of IL-1β. These findings identify a novel mechanism of host autophagy modulation and immune modulation employed by V. cholerae during bacterial infection.