Cholesterol of lipid rafts is a key determinant for entry and post-entry control of porcine rotavirus infection

Dou, Xiujing; Li, Yang; Han, Junlan; Zarlenga, Dante S.; Zhu, Wei; Ren, Xiaofeng; Dong, Na; Li, Xunliang; Li, Guangxing

doi:10.1186/s12917-018-1366-7

Cited by 38 publications

(38 citation statements)

References 38 publications

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“…Efficiency of cholesterol depletion was confirmed by showing that association of cholera toxin subunit B (CTB) with C10 and CHO-HVEM cells, which is dependent on membrane cholesterol (50), was decreased with MβCD treatment (S4F Fig). Entry of VSVΔG-G was insensitive to cholesterol depletion (S4A, C Fig), as observed in other cell types (51, 52). By contrast, cholesterol was important for VSVΔG-PIV5 entry into C10 cells (S4B Fig) but not into CHO-HVEM cells (S4D Fig), suggesting that the role of cellular cholesterol in PIV5 entry is cell-type dependent.…”

Section: Resultssupporting

confidence: 72%

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Hilterbrand

Daly

Heldwein

2020

Preprint

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15Herpes Simplex viruses (HSV-1 and HSV-2) encode up to 15 glycosylated and unglycosylated 16 envelope proteins. Four of these, gB, gH, gL, and gD, are essential for entry and mediate cell-cell 17 fusion when co-expressed in uninfected, receptor-bearing cells. However, their contributions to 18 HSV-1 tropism and the selection of entry routes are unclear. To begin addressing this, we 19 previously pseudotyped VSV lacking its native glycoprotein, G, with HSV-1 glycoproteins gB, 20 gH, gL, and gD. This novel VSVDG-BHLD pseudotype recapitulated several aspects of HSV-1 21 entry: it could enter murine C10 cells, required gB, gH, gL, gD, and a cellular receptor for entry, 22 AUTHOR SUMMARY 37Different viruses enter cells by diverse routes, but how that choice is made is not always clear. 38Understanding the mechanisms behind these choices is vital for finding strategies to prevent viral 39 infections. In enveloped viruses, viral proteins embedded in the envelope accomplish this task. 40While most enveloped viruses encode one or two envelope proteins, Herpes Simplex viruses 41 (HSV) encode up to 15. Four of these are deemed essential for entry (gB, gH, gL, and gD) 42 whereas the rest have been termed non-essential. While these four proteins are essential, their 43 contributions to HSV-1 cellular tropism and entry pathways have not been fully elucidated. Here, 44we generated virions that have only the four essential HSV-1 glycoproteins on their surface. We 45show that the VSVDG-BHLD pseudotype has a narrower tropism than HSV-1 and uses different 46 entry pathways. Thus, the four essential HSV-1 entry glycoproteins alone do not define HSV-1 47 55All viruses must enter cells to initiate infection, and different viruses accomplish this task by 56 different mechanisms: some penetrate cells at the plasma membrane while others hijack host 57 endocytic pathways. Enveloped viruses -those in which the nucleocapsid is surrounded by a 58 cell-derived lipid bilayer -penetrate the cells by merging their lipid envelopes with a cellular 59 membrane, either the plasma membrane or the membrane of an endocytic vesicle following 60 endocytosis ( Fig 1) [reviewed in (1, 2)]. Viruses typically have preferred entry routes, the choice 61 of which is not always clear, and some enter different target cells by different routes. 62Understanding what routes viruses use to enter cells and how they select them may help inform 63 strategies to prevent viral infections. 64Herpes Simplex viruses (HSV-1 and HSV-2) are enveloped alphaherpesviruses that infect 65 much of the world's population for life, causing a panoply of diseases ranging from painful to 66 life-threatening (3, 4). An enduring mystery of HSV entry is how and why the virus enters 67 different cells by different routes: direct fusion with the plasma membrane [e.g., neurons, Vero 68 cells, Hep2 cells, reviewed in (5)] or by endocytosis and subsequent fusion with the endosomal 69 membrane [e.g., keratinocytes, corneal epithelial cells (6, 7)]. 70HSV-1 encodes 15 viral envelope proteins, ...

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Section: Resultssupporting

confidence: 72%

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Hilterbrand

Daly

Heldwein

2020

Preprint

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“…Moreover, cholesterol-dependent processes play a key role in the development of many infectious diseases, since the interaction of the pathogen with the host cell in many cases occurs with the participation of cholesterol. For example, the entry of certain viruses [9,[13][14][15] and bacteria [16][17][18][19][20] into the cell depends on the presence of cholesterol and lipid rafts [15,16,21] in the membranes of the host cells. Understanding the molecular mechanisms of protein-cholesterol interactions and their role in cellular processes can provide the basis for the development of new methods for the prevention and treatment of such diseases.…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Cholesterol-Dependent Activity of Macrophages IC-21 by CRAC Peptides with Substituted Motif-Forming Amino Acids

Dunina-Barkovskaya

Vishnyakova

2020

Biochem. Moscow Suppl. Ser. A

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The activity of many membrane proteins, such as receptors, ionic channels, transporters, and enzymes, is cholesterol dependent; however, mechanisms of the cholesterol-dependent regulation of protein functions remain obscure. Recent studies suggest that membrane proteins can directly interact with cholesterol owing to the presence of the cholesterol-recognizing amino-acid consensus (CRAC) motifs. One of the ways to verify and further develop this notion is a design of CRAC-containing peptides and investigation of their effects on cholesterol-dependent cell functions. Previously we showed that a newly constructed peptide RTKLWEMLVELGNMDKAVKLWRKLKR (peptide P4) containing two CRAC motifs modulates cholesteroldependent interactions of cultured macrophages IC-21 with 2-μm particles. In this work, in order to clarify the role of CRAC-forming amino acids, we employed the same experimental system to test the activity of peptides closely related to P4 but with modified CRAC motifs. We found that peptide STKLSEMLSELGNMDKASKLSRKLSR (Mut2) analogous to P4, except that all CRAC-forming amino acids (V, W, K/R) were substituted by serine, did not produce any effect in the concentration range 0.5-50 μM corresponding to the range of the P4 activity. Neither was effective peptide RTKLSEMLVELGNMDKAVKLSRKLKR (Mut3), in which only aromatic amino acids (W) of the CRAC motifs were substituted. Peptide STKLWEMLVELGNMDKAVKLWRKLSR (Mut4), in which only cationic amino acids (R/K) in the CRAC motifs were changed, produced almost the same effect as that of peptide P4 with a bell-shape dose-response curve. At low concentrations (1-4 μM) Mut4 notably increased the number of beads per cell, at higher concentrations this parameter diminished, and at 50 μM Mut4 produced a robust toxic effect. Finally, peptide EWGMAVLWERNRKLKKDLKVLKMLRT (Mut1) composed of the same amino acid residues as P4 but in a random order ("scramble") and possessing one CRAC motif, different from that in P4, produced a moderate stimulation at 4-10 μM but was not toxic at 50 μM. As in the case of peptide P4, the effects of Mut4 and Mut1 depended on the cholesterol content in the cell membrane: after the incubation of cells with cholesterol-extracting agent methyl-β-cyclodextrin stimulatory effects produced by Mut4 and Mut1 at low doses were suppressed. Our results indicate that CRAC motifs play an important role in the mechanisms of the peptide-induced modulations of cholesterol-dependent cell functions in the experimental system used and that of the three motif-forming amino acids, critical is the presence of the aromatic amino acid (W). Further research is required to comprehend the molecular mechanisms of interactions of CRAC-containing peptides with cell membrane components that lead to modulation of cell functions. We anticipate that CRAC-containing peptides may provide a basis for the development of new tools for directed regulation of the activity of target cholesterol-dependent membrane proteins and for the design of new antimicrobial and immunomodulating drugs in par...

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“…In particular, lipid raft disruption by cholesterol-depleting agents has been shown to inhibit infection of several microbes by blocking their entry into the host cells (Nomura et al, 2004;Thorp and Gallagher, 2004;Choi et al, 2005;Riethmüller et al, 2006;Glende et al, 2008;Lu et al, 2008;Guo et al, 2017;Owczarek et al, 2018;Szczepanski et al, 2018;Abu-Farha et al, 2020;Baglivo et al, 2020;Fantini et al, 2020;Rodrigues-Diez et al, 2020; Table 1). In human immunodeficiency virus (Ono and Freed, 2001), herpes simplex virus, and rotavirus infections, MβCD, a widely used raft-disrupting agent, has been shown to affect virus entry, thereby reducing their infectivity (Dou et al, 2018;Wudiri et al, 2017). In addition, in Japanese encephalitis virus and dengue virus infection, disruption of lipid rafts by MβCD has been shown to decrease viral infection acting at both viral entry and intracellular replication step (Lee et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Coronavirus Interplay With Lipid Rafts and Autophagy Unveils Promising Therapeutic Targets

et al. 2020

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Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses that can infect animal and human hosts. The infection induces mild or sometimes severe acute respiratory diseases. Nowadays, the appearance of a new, highly pathogenic and lethal coronavirus variant, SARS-CoV-2, responsible for a pandemic (COVID-19), represents a global problem for human health. Unfortunately, only limited approaches are available to treat coronavirus infections and a vaccine against this new coronavirus variant is not yet available. The plasma membrane microdomain lipid rafts have been found by researchers to be involved in the replication cycle of numerous viruses, including coronaviruses. Indeed, some pathogen recognition receptors for coronaviruses as for other viruses cluster into lipid rafts, and it is therefore conceivable that the first contact between virus and host cells occurs into these specialized regions, representing a port of cell entry for viruses. Recent data highlighted the peculiar pro-viral or anti-viral role played by autophagy in the host immune responses to viral infections. Coronaviruses, like other viruses, were reported to be able to exploit the autophagic machinery to increase their replication or to inhibit the degradation of viral products. Agents known to disrupt lipid rafts, such as metil-β-cyclodextrins or statins, as well as autophagy inhibitor agents, were shown to have an anti-viral role. In this review, we briefly describe the involvement of lipid rafts and autophagy in coronavirus infection and replication. We also hint how lipid rafts and autophagy may represent a potential therapeutic target to be investigated for the treatment of coronavirus infections.

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Cholesterol of lipid rafts is a key determinant for entry and post-entry control of porcine rotavirus infection

Cited by 38 publications

References 38 publications

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Contributions of the four essential entry glycoproteins to HSV-1 tropism and the selection of entry routes

Modulation of the Cholesterol-Dependent Activity of Macrophages IC-21 by CRAC Peptides with Substituted Motif-Forming Amino Acids

Coronavirus Interplay With Lipid Rafts and Autophagy Unveils Promising Therapeutic Targets

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