Tag Archive for: cholesterol

Publication on AWSensors technology

Lipid packing frustration in the outer leaflet of the plasma membrane prevents scission of caveolae

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Authors: Elin Larsson, Aleksei Kabedev, Hudson Pace, Jakob Lindwall, Fouzia Bano, Robert G Parton, Christel A. S. Bergstrom, Ingela Parmryd, Marta Bally, Richard Lundmark

Journal: bioRxiv

Abstract: Lipid packing is a fundamental characteristic of bilayer membranes. It affects all membrane-associated processes ranging from curvature generation to membrane fission. Yet, we lack detailed, mechanistic understanding of how lipid packing directly affects these processes in cellular membranes. Here, we address this by focusing on caveolae, small Ω-shaped invaginations of the plasma membrane which serve as key regulators of cellular lipid sorting and mechano-responses. In addition to caveolae coat proteins, the lipid membrane is a core component of caveolae that critically impacts both the biogenesis, morphology and stability of such membrane invaginations. We show that the small compound Dyngo-4a inserts into the membrane, resulting in a dramatic dynamin-independent inhibition of caveola scission. Analysis of model membranes in combination with molecular dynamics simulations revealed that a substantial amount of Dyngo-4a was inserted and positioned at the level of cholesterol in the bilayer. Dyngo-4a-treatment resulted in decreased lipid packing in the outer leaflet of the plasma membrane preventing scission without affecting caveola morphology, caveolae- associated proteins, or the overall membrane stiffness. Artificially increasing plasma membrane cholesterol levels was found to counteract the block in caveola scission caused by Dyngo-4a-mediated lipid packing frustration. Therefore, we propose that the packing of cholesterol in the outer leaflet of the plasma membrane critically controls the confinement of caveolae to the plasma membrane.

The full article can be accessed here.

Publication on AWSensors technology

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

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Authors: Xiaotong Jia, Anastasia Knyazeva, Yu Zhang, Sergio Castro-Gonzalez, Shuhei Nakamura, Lars-Anders Carlson, Tamotsu Yoshimori, Dale P. Corkery, Yao-Wen Wu

Journal: J Cell Biol (2022)

 

Abstract

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

You may read the full paper here.