V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy

• DOI: 10.1083/jcb.202206040
• Publication Date: 2022-10-04T13:13:52Z
• Authors: Xiaotong Jia; Anastasia Knyazeva; Yu Zhang; Sergio Castro-Gon...; Shuhei Nakamura; Lars-Anders Carlson; Tamotsu Yoshimori; Dale P. Corkery; Yao-Wen Wu
• Keywords: Lipid-anchored protein; Internalization; Pore-forming toxin; Cholera toxin; Virulence factor

Pore-forming toxins (PFTs) are important virulence factors produced by many pathogenic bacteria. Here, we show that the Vibrio cholerae toxin MakA is a novel cholesterol-binding PFT induces non-canonical autophagy in pH-dependent manner. specifically binds to cholesterol on membrane at pH < 7. Cholesterol-binding leads oligomerization of and pore formation 5.5. Unlike other cholesterol-dependent cytolysins (CDCs) which bind through conserved motif (Thr-Leu pair), contains an Ile-Ile pair essential for MakA-cholesterol interaction. Following internalization, endosomal acidification triggers pore-assembly followed ESCRT-mediated repair V-ATPase-dependent unconventional LC3 lipidation damaged endolysosomal membranes. These findings characterize new forms pores manner reveals molecular mechanism host manipulation.