Tetraspanin CD151 Mediates Papillomavirus Type 16 Endocytosis

Scheffer, Konstanze D.; Gawlitza, Alexander; Spoden, Gilles A.; Zhang, Xin A.; Lambert, Carsten; Berditchevski, Fedor; Florin, Luise

doi:10.1128/jvi.02906-12

Cited by 116 publications

(181 citation statements)

References 73 publications

(100 reference statements)

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“…For example, CD81 and TSPAN9 have been recently identified in genome-wide small interfering (si)RNA screens for host factors that regulate the early steps of influenza virus and Alphavirus infection, respectively (Karlas et al, 2010;Kö nig et al, 2010;Ooi et al, 2013); it has also been suggested that CD81 and TSPAN9 regulate viral fusion in endosomes (He et al, 2013;Ooi et al, 2013). CD151 has been shown to contribute to the endocytosis of the human papillomavirus (HPV)16, an etiologic agent for cervical cancers (Scheffer et al, 2013). This function of CD151 requires an interaction with integrins (integrin a6 has previously been identified as a receptor for HPV) and its palmitoylation (and so presumably interaction with other tetraspanins).…”

Section: Box 1 Tetraspanins In Infectious Diseasesmentioning

confidence: 99%

Tetraspanins at a glance

Charrin

Jouannet

Boucheix

et al. 2014

Journal of Cell Science

371

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Tetraspanins are a family of proteins with four transmembrane domains that play a role in many aspects of cell biology and physiology; they are also used by several pathogens for infection and regulate cancer progression. Many tetraspanins associate specifically and directly with a limited number of proteins, and also with other tetraspanins, thereby generating a hierarchical network of interactions. Through these interactions, tetraspanins are believed to have a role in cell and membrane compartmentalization. In this Cell Science at a Glance article and the accompanying poster, we describe the basic principles underlying tetraspaninbased assemblies and highlight examples of how tetraspanins regulate the trafficking and function of their partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system.

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Section: Box 1 Tetraspanins In Infectious Diseasesmentioning

confidence: 99%

Tetraspanins at a glance

Charrin

Jouannet

Boucheix

et al. 2014

Journal of Cell Science

371

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“…Endocytosis of viral particles is mediated by a clathrin-, dynamin-, and caveolin-independent mechanism but requires tetraspanin CD151 and the actin cytoskeleton (10,27,28,(31)(32)(33)(34). Following internalization, viral particles are found in CD63-positive endosomes recruiting syntenin-1, a CD63-interacting adaptor protein (35).…”

mentioning

confidence: 99%

“…Furin cleavage may also occur during virion morphogenesis, as shown for tissue-derived native HPV16, resulting in infection independent of cellular furin (25). The precleaved virus is transferred to tetraspanin-enriched microdomains (TEMs) (27,28), where L2 directly interacts with the annexin A2 heterotetramer (A2t), a protein localized on the outer and inner leaflet of the plasma membrane and mediating viral endocytosis and infection (29,30). Interaction occurs be- Citation Wüstenhagen E, Hampe L, Boukhallouk F, Schneider MA, Spoden GA, Negwer I, Koynov K, Kast WM, Florin L. 2016.…”

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confidence: 99%

The Cytoskeletal Adaptor Obscurin-Like 1 Interacts with the Human Papillomavirus 16 (HPV16) Capsid Protein L2 and Is Required for HPV16 Endocytosis

Wüstenhagen

Hampe

Boukhallouk

et al. 2016

J Virol

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The human papillomavirus (HPV) capsid protein L2 is essential for viral entry. To gain a deeper understanding of the role of L2, we searched for novel cellular L2-interacting proteins. A yeast two-hybrid analysis uncovered the actin-depolymerizing factor gelsolin, the membrane glycoprotein dysadherin, the centrosomal protein 68 (Cep68), and the cytoskeletal adaptor protein obscurin-like 1 protein (OBSL1) as putative L2 binding molecules. Pseudovirus (PsV) infection assays identified OBSL1 as a host factor required for gene transduction by three oncogenic human papillomavirus types, HPV16, HPV18, and HPV31. In addition, we detected OBSL1 expression in cervical tissue sections and noted the involvement of OBSL1 during gene transduction of primary keratinocytes by HPV16 PsV. Complex formation of HPV16 L2 with OBSL1 was demonstrated in coimmunofluorescence and coimmunoprecipitation studies after overexpression of L2 or after PsV exposure. We observed a strong colocalization of OBSL1 with HPV16 PsV and tetraspanin CD151 at the plasma membrane, suggesting a role for OBSL1 in viral endocytosis. Indeed, viral entry assays exhibited a reduction of viral endocytosis in OBSL1-depleted cells. Our results suggest OBSL1 as a novel L2-interacting protein and endocytosis factor in HPV infection. IMPORTANCEHuman papillomaviruses infect mucosal and cutaneous epithelia, and the high-risk HPV types account for 5% of cancer cases worldwide. As recently discovered, HPV entry occurs by a clathrin-, caveolin-, and dynamin-independent endocytosis via tetraspanin-enriched microdomains. At present, the cellular proteins involved in the underlying mechanism of this type of endocytosis are under investigation. In this study, the cytoskeletal adaptor OBSL1 was discovered as a previously unrecognized interaction partner of the minor capsid protein L2 and was identified as a proviral host factor required for HPV16 endocytosis into target cells. The findings of this study advance the understanding of a so far less well-characterized endocytic pathway that is used by oncogenic HPV subtypes. Human papillomaviruses (HPVs) are small, nonenveloped DNA viruses that infect dividing basal keratinocytes of skin and mucosa via microlesions of the tissue. HPV is capable of inducing benign epithelial warts on the skin and mucosa, and infection with a high-risk HPV type may cause cervical and other anogenital and oropharyngeal cancers (1, 2). Cervical cancer is the third most common cancer in women worldwide and is associated with HPV infection, more precisely with high-risk HPV types such as HPV16, HPV18, and HPV31 (3). HPV is composed of a viral capsid with the major capsid protein L1, the minor capsid protein L2, and the viral genome. One icosahedral capsid contains 360 copies of L1, which can self-assemble to 72 pentamers, and up to 72 copies of the minor capsid protein L2, located inside the L1 shell (4-6). The capsid proteins L1 and L2 are key players in early events of infection, such as virus binding at the plasma membrane, cell entry, and t...

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“…Following primary attachment and internalization, acidification of early endosomes triggers capsid disassembly (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Host cell cyclophilins release the majority of L1 from the L2 protein, which remains in complex with the viral genome (2,23,24).…”

mentioning

confidence: 99%

Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis

DiGiuseppe

Luszczek

Keiffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

140

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During the entry process, the human papillomavirus (HPV) capsid is trafficked to the trans-Golgi network (TGN), whereupon it enters the nucleus during mitosis. We previously demonstrated that the minor capsid protein L2 assumes a transmembranous conformation in the TGN. Here we provide evidence that the incoming viral genome dissociates from the TGN and associates with microtubules after the onset of mitosis. Deposition onto mitotic chromosomes is L2-mediated. Using differential staining of an incoming viral genome by small molecular dyes in selectively permeabilized cells, nuclease protection, and flotation assays, we found that HPV resides in a membrane-bound vesicle until mitosis is completed and the nuclear envelope has reformed. As a result, expression of the incoming viral genome is delayed. Taken together, these data provide evidence that HPV has evolved a unique strategy for delivering the viral genome to the nucleus of dividing cells. Furthermore, it is unlikely that nuclear vesicles are unique to HPV, and thus we may have uncovered a hitherto unrecognized cellular pathway that may be of interest for future cell biological studies.HPV entry | vesicular transport | mitosis | digitonin | nuclear vesicle A major hurdle of DNA viruses during a primary infection is successful navigation of the cytoplasm to deliver the viral genome to the nucleus. Foreign DNA that enters the cytoplasm is susceptible to being sensed by innate immune sensors (1). Not surprisingly, viruses have evolved mechanisms to evade detection by these sensors. For example, herpesviruses and adenoviruses both egress into the cytoplasm, yet protect their viral DNA by keeping it encased in viral capsids until directly transferring it into the nucleus through the nuclear pore complex. In contrast, the capsid is unlikely to protect papillomavirus (PV) genomes while traversing the cytoplasm, because the major capsid protein is lost in the endocytic compartment (2).The PV capsid is composed of two viral proteins, the major capsid protein L1 and the minor capsid protein L2, which enclose a chromatinized, circular, double-stranded DNA genome ∼8 kb in size (3-6). Following primary attachment and internalization, acidification of early endosomes triggers capsid disassembly (7-22). Host cell cyclophilins release the majority of L1 from the L2 protein, which remains in complex with the viral genome (2,23,24). A large portion of the L2 protein translocates across the endocytic membrane to engage factors, including the retromer complex, dynein, sorting nexins, and rab GTPases, that mediate transport to the trans-Golgi network (TGN) (25)(26)(27)(28)(29)(30)(31)(32)(33)). An siRNA screen has suggested that nuclear pore complexes are not required for nuclear entry, but that nuclear envelope breakdown during mitosis is necessary (34, 35).Currently, when and how the human PV (HPV) genome egresses from the membranous compartment is unclear. Here we present evidence indicating that after the onset of mitosis, the viral genome of HPV type 16 (HPV16), an HPV type...

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Tetraspanin CD151 Mediates Papillomavirus Type 16 Endocytosis

Cited by 116 publications

References 73 publications

Tetraspanins at a glance

Tetraspanins at a glance

The Cytoskeletal Adaptor Obscurin-Like 1 Interacts with the Human Papillomavirus 16 (HPV16) Capsid Protein L2 and Is Required for HPV16 Endocytosis

Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis

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