Interplay of lipid head group and packing defects in driving amyloid-beta–mediated myelin-like model membrane deformation

Tiwari, Anuj; Pradhan, Sweta; Sannigrahi, Achinta; Mahakud, Amaresh Kumar; Jha, Suman; Chattopadhyay, Krishnananda; Biswas, Mithun; Saleem, Mohammed

doi:10.1016/j.jbc.2023.104653

Cited by 3 publications

(5 citation statements)

References 72 publications

(91 reference statements)

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“…3c). Such puncta are often related to the aggregated forms of the proteins as reported earlier for ESAT-6 as well as other amyloidogenic proteins [42][43][44]. Subsequently, the phagosome numbers decrease over a few hours, suggesting the disruption and cytosolic access of the ESAT-6 (Fig.…”

Section: Esat-6 Fibrillation Drives the Rate Of Vesiculation Of The P...supporting

confidence: 66%

“…It is possible that the ESAT-6 gets pinocytosed and subsequently fibrillates and deforms the phagosomal membrane to gain access to the cytosol where it continues to polymerize. It is important to note that until the equilibrium phase is reached ESAT-6 would exist as a mixture of monomers, oligomers, and fibrils all of which can bind to the membrane with different affinities 37 . Both the high surface density of the protein and the growing network of polymerizing protein are known to exert forces on the membranes resulting in local modulation of curvature and tension 38, 65–68 .…”

Section: Discussionmentioning

confidence: 99%

“…An important reason behind the observed membrane-spanning pore-forming conformation could be the usage of oversimplified lipid composition, that is, DOPC. The packing density arising due to the cylindrical geometry of the DOPC may facilitate the deep insertion of the ESAT-6 54 but might not be the case for a complex multi-component biological membrane 37 . On the contrary, we show that ESAT-6 inserts only until C5 of the acyl chain, on biologically relevant phagosomal membrane mimic comprising lipid composition of complex geometry.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, we observe that ESAT-6 fibrillates in the presence of phagosome membrane interface that slows down the fibrillation kinetics and forms a mesh-like network at the equilibrium phase (Fig 3ac, 3h-i). It is important to note that until the equilibrium phase is reached, ESAT-6 would exist as a mixture of monomers, oligomers, and fibrils, all of which can bind to the membrane with different affinities and deform the membrane [42,44]. Both the high surface density of the protein and the growing network of polymerizing protein are known to exert forces on the membranes resulting in local modulation of curvature and tension [45,[75][76][77][78].…”

Section: Discussionmentioning

confidence: 99%

“…3a). Certain lipids have been found to inhibit or retard the fibrillation kinetics of several amyloidogenic proteins [42] that might explain the observed slowdown in fibrillation kinetics. Further, no fibrillation of CFP-10 was observed in solution or in the presence of membrane confirming the specificity of ESAT-6 fibrillation (Extended Data Fig.…”

Section: Esat-6 Fibrillation Drives the Rate Of Vesiculation Of The P...mentioning

confidence: 99%

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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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Section: Esat-6 Fibrillation Drives the Rate Of Vesiculation Of The P...supporting

confidence: 66%