Revisiting Membrane Microdomains and Phase Separation: A Viral Perspective

Sengupta, Prabuddha; Lippincott‐Schwartz, Jennifer

doi:10.3390/v12070745

Cited by 25 publications

(18 citation statements)

References 96 publications

(120 reference statements)

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“…[ 220 , 221 , 222 , 223 ]. The druggability of lipid-based pathogen–host interactions has been reviewed extensively elsewhere [ 224 , 225 , 226 , 227 ].…”

Section: Alterations In the Lipid Composition Of Membranes—opportunities For Clinical Exploitationmentioning

confidence: 99%

Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

Fritsch

Särchen

Schneider-Brachert

2021

Cancers

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Death-receptor-mediated signaling results in either cell death or survival. Such opposite signaling cascades emanate from receptor-associated signaling complexes, which are often formed in different subcellular locations. The proteins involved are frequently post-translationally modified (PTM) by ubiquitination, phosphorylation, or glycosylation to allow proper spatio-temporal regulation/recruitment of these signaling complexes in a defined cellular compartment. During the last couple of years, increasing attention has been paid to the reversible cysteine-centered PTM S-palmitoylation. This PTM regulates the hydrophobicity of soluble and membrane proteins and modulates protein:protein interaction and their interaction with distinct membrane micro-domains (i.e., lipid rafts). We conclude with which functional and mechanistic roles for S-palmitoylation as well as different forms of membrane micro-domains in death-receptor-mediated signal transduction were unraveled in the last two decades.

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“…[ 220 , 221 , 222 , 223 ]. The druggability of lipid-based pathogen–host interactions has been reviewed extensively elsewhere [ 224 , 225 , 226 , 227 ].…”

Section: Alterations In the Lipid Composition Of Membranes—opportunities For Clinical Exploitationmentioning

confidence: 99%

Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

Fritsch

Särchen

Schneider-Brachert

2021

Cancers

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“…The ability of a virus to cluster is important for its infectivity and maturation 39–42 . For SARS-CoV2 entry depends on binding to ACE2.…”

Section: Resultsmentioning

confidence: 99%

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

Yuan

Pavel

Wang

et al. 2020

Preprint

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Background: SARS-coronavirus 2 (SARS-CoV-2) is currently causing a worldwide pandemic. Potential drugs identified for the treatment of SARS-CoV-2 infection include chloroquine (CQ), its derivative hydroxychloroquine (HCQ), and the anesthetic propofol. Their mechanism of action in SARS-CoV-2 infection is poorly understood. Recently, anesthetics, both general and local, were shown to disrupt ordered lipid domains. These same lipid domains recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to an endocytic entry point and their disruption by cholesterol depletion decreases ACE2 recruitment and viral entry. Methods: Viral entry was determined using a SARS-CoV-2 pseudovirus (SARS2-PV) and a luciferase reporter gene expressed by the virus after treatment of the cells with 50 micromolar propofol, tetracaine, HCQ, and erythromycin. HCQ disruption of monosialotetrahexosylganglioside1 (GM1) lipid rafts, phosphatidylinositol 4,5-bisphosphate (PIP2) domains, and ACE2 receptor at nanoscale distances was monitored by direct stochastic reconstruction microscopy (dSTORM). Cells were fixed, permeabilized, and then labeled with either fluorescent cholera toxin B (CTxB) or antibody and then fixed again prior to imaging. Cluster analysis of dSTORM images was used to determine size and number and cross pair correlation was used to determine trafficking of endogenously expressed ACE2 in and out of lipid domains. Results: Propofol, tetracaine, and HCQ inhibit SARS2-PV viral entry. HCQ directly perturbs both GM1 lipid rafts and PIP2 domains. GM1 rafts increased in size and number similar to anesthetic disruption of lipid rafts; PIP2 domains decreased in size and number. HCQ blocked both GM1 and PIP2 domains ability to attract and cluster ACE2. Conclusions: We conclude HCQ is an anesthetic-like compound that disrupts GM1 lipid rafts similar to propofol and other local or general anesthetics. Furthermore, we conclude disruption of GM1 raft function, and not the concentration of GM1 raft molecules, governs the antiviral properties of HCQ. HCQ disruption of the membrane appears to also disrupt the production of host defense peptide, hence an antimicrobial such as erythromycin could be an important combined treatment. Nonetheless erythromycin has anti-SARS-CoV-2 activity and may combine with HCQ to reduce infection.

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“…In turn, lateral lipid sorting alters the local mechanical and structural properties of the membrane. [48][49][50] Binding of pMLKL oligomers to defined regions of the plasma membrane and further rearrangement of the local lipid distribution at their binding site allows high concentration of fatty acids that covalently modify pMLKL. Acylation of pMLKL oligomers would allow the local recruitment of VLCFAs to membrane regions that already possess different mechanical and structural properties, which facilitates their membrane disruption action.…”

Section: Discussion/conclusionmentioning

confidence: 99%