Common principles of surface deformation in biology

Roux, Aurélien

doi:10.1039/d1fd00040c

Cited by 1 publication

(1 citation statement)

References 38 publications

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“…2jk). The observed tubulations and buds can be attributed to the changes in local membrane curvature and lateral pressure introduced as a result of high surface density and shallow insertion of ESAT-6 pushing away the lipid-head groups in the interacting membrane leaflet [66][67][68][69]. Indeed the magnitude of the protein-inducedmembrane bending and curvature generation is known to non-monotonously depend on the insertion depth of the protein for biologically relevant conditions [68,70].…”

Section: Discussionmentioning

confidence: 99%

Real-time visualization reveals Mycobacterium tuberculosis ESAT-6 disrupts phagosome via fibril-mediated vesiculation

Koiri,

Nandi,

Abik Hameem

et al. 2024

Preprint

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Mycobacterium tuberculosis (Mtb) evades host defense by hijacking and rupturing the phagosome, enabling it to escape to the host cytosol for its survival. ESAT-6, a secreted virulence protein of Mtb, is known to be critical for phagosome rupture. However, the mechanism of ESAT-6-mediated disruption of the phagosomal membrane remains unknown. Using in vitro reconstitution and numerical simulations, we discover that ESAT-6 polymerization remodels and vesiculates phagosomal membrane. In sharp contrast to the canonical pore formation triggered by a bilayer-spanning conformation, we find that the binding of ESAT-6 to the phagosomal membrane is shallow. Such shallow insertion leads to membrane shape transition leading to tubular and bud-like deformations on the membrane in a concentration-dependent manner, facilitated by the reduction in membrane tension and compressibility modulus. Strikingly, our observations suggest that ESAT-6 polymerizes in bulk and on the membrane, both in vitro and in macrophage. Numerical simulations demonstrate that growing fibrils generate both radial and tangential forces causing local remodeling and shape transition of the membrane. Using micropipette aspiration, we quantitatively show that ESAT-6 bound tensed membrane undergoes local changes in membrane curvature and lipid phase separation, also facilitated by the direct contact of the bacteria inside the phagosome. Nonetheless, the vesiculation of the buds is primarily driven by the forces exerted by the polymerization of ESAT-6. Such ESAT-6 mediated vesiculation induces apoptosis and host cell death in a concentration and time-dependent manner that promotes infection. Overall, the findings provide mechanistic insights into the long-standing question of phagosome disruption by Mtb for its escape.

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