Biology subjects

Corkery, D.

Publications and source records attributed to Corkery, D..

2 recordsLinked to original sources

bioRxiv2023

Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomes

The Endosomal Sorting Complex Required for Transport (ESCRT) machinery constitutes a multisubunit protein complex that plays an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, encompassing cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair and autophagy. Given the versatile functionality of ESCRTs and the intricate organizational structure of the ESCRT complex, the targeted modulation of distinct ESCRT-mediated membrane deformations for functional dissection poses a considerable challenge. This study presents a pseudo-natural product targeting IST1-CHMP1B within the ESCRT-III complex. This compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting and exosome biogenesis, it rapidly hinders transferrin receptor (TfR) recycling in cells, resulting in the accumulation of transferrin in perinuclear endosomal recycling tubules. Stalled recycling endosomes acquire unconventional LC3 lipidation, establishing a link between non-canonical LC3 lipidation and endosomal recycling.

cell biology↗

bioRxiv2020

The Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy

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 subversion 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 subversion and immune modulation employed by V. cholerae during bacterial infection.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗