Tetraspanin Assemblies in Virus Infection

Florin, Luise; Lang, Thorsten

doi:10.3389/fimmu.2018.01140

Cited by 99 publications

(94 citation statements)

References 128 publications

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“…This is in line with studies having shown that in contrast to hepatocytes, other cell types which are not susceptible to HCV express distinct CD81 partners that restrict HCV entry [114][115][116]. Interestingly, tetraspanin assemblies are emerging as key platforms regulating the entry of unrelated viruses [117][118][119].…”

Section: The Regulatory Role Of Cd81-tetraspanin Platformssupporting

confidence: 82%

Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

Colpitts

Tsai

Zeisel

2020

IJMS

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Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver disease worldwide. Its tissue and species tropism are largely defined by the viral entry process that is required for subsequent productive viral infection and establishment of chronic infection. This review provides an overview of the viral and host factors involved in HCV entry into hepatocytes, summarizes our understanding of the molecular mechanisms governing this process and highlights the therapeutic potential of host-targeting entry inhibitors.

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Section: The Regulatory Role Of Cd81-tetraspanin Platformssupporting

confidence: 82%

Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

Colpitts

Tsai

Zeisel

2020

IJMS

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“…In the context of host-pathogen interaction, CD9enriched microdomains have been described as important host cell factors in infections by various viruses [24]. Likewise, our comparative analyses on the function of different tetraspanins and tetraspanin domains implicated a crucial role of CD9 in HPV16 infection of HeLa cells [19].…”

Section: Introductionmentioning

confidence: 57%

“…These molecules are announced as plasma membrane "master organizers" due to their ability to interact with multiple plasma membrane molecules and to form functional tetraspanin-enriched microdomains [21][22][23]. From the 33 tetraspanins identified in humans so far, only a portion has been shown to play an important role in regulating the entry process of various viruses including CD9, CD63, CD81 and CD151 [24,25].…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin CD9 affects HPV16 infection by modulating ADAM17 activity and the ERK signalling pathway

Mikuličić

Fritzen

Scheffer

et al. 2020

Med Microbiol Immunol

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Human papillomaviruses (HPV) are causative agents of various tumours such as cervical cancer. HPV binding to the cell surface of keratinocytes leads to virus endocytosis at tetraspanin enriched microdomains. Complex interactions of the capsid proteins with host proteins as well as ADAM17-dependent ERK1/2 signal transduction enable the entry platform assembly of the oncogenic HPV type 16. Here, we studied the importance of tetraspanin CD9, also known as TSPAN29, in HPV16 infection of different epithelial cells. We found that both overexpression and loss of the tetraspanin decreased infection rates in cells with low endogenous CD9 levels, while reduction of CD9 expression in keratinocytes that exhibit high-CD9 protein amounts, led to an increase of infection. Therefore, we concluded that low-CD9 supports infection. Moreover, we found that changes in CD9 amounts affect the shedding of the ADAM17 substrate transforming growth factor alpha (TGFα) and the downstream phosphorylation of ERK. These effects correlate with those on infection rates suggesting that a specific CD9 optimum promotes ADAM17 activity, ERK signalling and virus infection. Together, our findings implicate that CD9 regulates HPV16 infection through the modulation of ADAM17 sheddase activity.

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“…Here, HPV particles associate with large CD151 patches to which they remain bound to, until they co-internalize with them 4,5 . Additionally, HPVs associate with aggregates of other tetraspanins 3,6 and several other viruses colocalize with tetraspanin patches or use tetraspanin assemblies for cell entry as well [7][8][9] . These observations lead to the proposal that virus contact with the cell membrane triggers the formation of tetraspanin-based virus entry platforms 6 .…”

Section: Anatomy Of a Viral Entry Platform Differentially Functionalimentioning

confidence: 99%

“…Additionally, HPVs associate with aggregates of other tetraspanins 3,6 and several other viruses colocalize with tetraspanin patches or use tetraspanin assemblies for cell entry as well [7][8][9] . These observations lead to the proposal that virus contact with the cell membrane triggers the formation of tetraspanin-based virus entry platforms 6 . Such viral entry platforms would require at least two functionalities: attachment and internalization of the virus.…”

Section: Anatomy Of a Viral Entry Platform Differentially Functionalimentioning

confidence: 99%

Anatomy of a viral entry platform differentially functionalized by integrins α3 and α6

Finke

Mikuličić

Loster

et al. 2020

Sci Rep

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www.nature.com/scientificreports www.nature.com/scientificreports/ cluster increases at viral particle attachment sites. Our data suggests that viral particles use an entry platform containing integrin α6 for virus attachment and integrin α3 for internalisation. Resultsintegrin α3 is required for HPV16 infection of keratinocytes. To clarify the role of integrin α3 in the infection of keratinocytes, we infected integrin α3 depleted HaCaT cells by incubation with HPV16 pseudovirions (PsVs). For positive control, cells were depleted from integrin α6, which is required for infection of HeLa and KH-SV cells 5,21 . In Western blot analysis, knockdown reduced integrin α6 and integrin α3 protein levels by 87% and 97%, respectively ( Fig. S1). Intracellular processing of the L1 virus capsid protein was monitored by Western blot analysis and by microscopy. In the Western blots, we quantified the ~25 kDa cleavage product of L1, which is generated only after internalization and lysosomal degradation of the virus 22 . As seen in Fig. 1A, knockdown of integrin α3 and integrin α6 reduced the cleavage product by 73% and 44%, respectively. For microscopy, we employed antibody-detection of the L1-7 epitope, which only becomes detectable after intracellular capsid disassembly 4,23 . Knockdown of either one of the integrins reduced the number of L1-7 positive organelles to about 65% ( Fig. 1B,C). Moreover, organelles were slightly dimmer ( Fig. S2), suggesting that apart from less forming endocytic organelles the viral load per organelle diminishes.Next, we employed a luciferase-based infection assay to test whether less uptake and processing of the L1 protein would be associated with a lower infection rate. Infection is inhibited by 88% and 67% after integrin α3 and integrin α6 knockdown, respectively ( Fig. 1D). It should be noted that integrin knockdown has secondary effects ( Fig. S3). Still, after correcting for these secondary effects, knockdown of each integrin more than halves the infection rate ( Fig. S3). These experiments demonstrate that apart from integrin α6, integrin α3 plays a role in HPV infection of HaCaT cells as well. However, in Western blot analysis testing PsVs cell-surface primary binding only the knockdown of integrin α6 strongly inhibits binding by 40% ( Fig. 2), suggesting each of these integrins is differently involved during infection.PsVs associate with cluster crowds. Next, we asked whether PsV particles are closer to their potential binding partner integrin α6, and analysed the distances between PsVs and CD151/integrin maxima. On membrane sheets, PsVs are often close to or overlap with CD151 or integrin α6 maxima (Fig. 4A,B). Most distances are in the range of several 100 nm ( Fig. 4C), with no trend towards shorter distances to integrin α6 maxima. Also, no maxima preference is observed on PsVs/CD151/integrin α3 stainings of cells ( Fig. 4D-F), or PsVs/ CD151-GFP/integrin α3 stainings on membrane sheets (Fig. S11). Moreover, it should be noted that PsVs diminish the level of CD151 and integrins by 10-...

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Tetraspanin Assemblies in Virus Infection

Cited by 99 publications

References 128 publications

Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

Tetraspanin CD9 affects HPV16 infection by modulating ADAM17 activity and the ERK signalling pathway

Anatomy of a viral entry platform differentially functionalized by integrins α3 and α6

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