Extracellular Conformational Changes in the Capsid of Human Papillomaviruses Contribute to Asynchronous Uptake into Host Cells

Becker, Miriam; Greune, Lilo; Schmidt, M. Alexander; Schelhaas, Mario

doi:10.1128/jvi.02106-17

Cited by 40 publications

(52 citation statements)

References 98 publications

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“…Recent studies have shown the importance of KLK8 during viral infections, such as those produced by the human papillomavirus (HPV). It has been proposed that KLK8 is involved in the entry of the virus into the cells through the proteolytic cleavage of L1 protein, the main capsid protein of HPV (Cerqueira et al, 2015;Becker et al, 2018). Remarkably, viral agents like HPV are believed to participate in the pathogenesis of multiple sclerosis where viral components act as a short-term risk factor for multiple sclerosis onset or relapse in the established disease.…”

Section: Klks Associated To Viral Infections That Can Affect the Cnsmentioning

confidence: 99%

Involvement of Kallikrein-Related Peptidases in Nervous System Disorders

Mella

Figueroa

Otth

et al. 2020

Front. Cell. Neurosci.

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Kallikrein-related peptidases (KLKs) are a family of serine proteases that when dysregulated may contribute to neuroinflammation and neurodegeneration. In the present review article, we describe what is known about their physiological and pathological roles with an emphasis on KLK6 and KLK8, two KLKs that are highly expressed in the adult central nervous system (CNS). Altered expression and activity of KLK6 have been linked to brain physiology and the development of multiple sclerosis. On the other hand, altered levels of KLK6 in the brain and serum of people affected by Alzheimer's disease and Parkinson's disease have been documented, pointing out to its function in amyloid metabolism and development of synucleinopathies. People who have structural genetic variants of KLK8 can suffer mental illnesses such as intellectual and learning disabilities, seizures, and autism. Increased expression of KLK8 has also been implicated in schizophrenia, bipolar disorder, and depression. Also, we discuss the possible link that exists between KLKs activity and certain viral infections that can affect the nervous system. Although little is known about the exact mechanisms that mediate KLKs function and their participation in neuroinflammatory and neurodegenerative disorders will open a new field to develop novel therapies to modulate their levels and/or activity and their harmful effects on the CNS.

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Section: Klks Associated To Viral Infections That Can Affect the Cnsmentioning

confidence: 99%

Involvement of Kallikrein-Related Peptidases in Nervous System Disorders

Mella

Figueroa

Otth

et al. 2020

Front. Cell. Neurosci.

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“…Given that furin-processing at the cell surface is requisite for successful infection and partially dictates the asynchronous uptake of HPV virions ( 39 , 40 ), we sought to assess whether RTD-1 would still be able to inhibit fpc HPV16 PsV. We found that fpcPsV are just as sensitive to RTD-1 inhibition as regular PsV ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering

et al. 2020

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Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing α and β defensins from humans has demonstrated that the α-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are θ-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype θ-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes.

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“…Studies employing co-immunoprecipitation and flow cytometry indicate that HPV binds directly to integrin α6 [11][12][13] . On the other hand, it is also assumed that the HPV capsid protein binds to a set of primary receptors different from integrin α6 16,39 , undergoes conformational changes and is then transferred to a secondary receptor complex 34,[48][49][50] which could be part of a TEM. Our experiments do not allow to differentiate between these binding states which may coexist in the same cell membrane.…”

Section: Scientific Reports |mentioning

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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Extracellular Conformational Changes in the Capsid of Human Papillomaviruses Contribute to Asynchronous Uptake into Host Cells

Cited by 40 publications

References 98 publications

Involvement of Kallikrein-Related Peptidases in Nervous System Disorders

Involvement of Kallikrein-Related Peptidases in Nervous System Disorders

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering

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

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