Med Microbiol Immunol DOI 10.1007/s00430-012-0262-1
REVIEW
Principles of polyoma- and papillomavirus uncoating Carla Cerqueira • Mario Schelhaas
Received: 23 August 2012 / Accepted: 23 August 2012 Ó Springer-Verlag 2012
Abstract Virus particles are vehicles for transmission of the viral genetic information between infected and uninfected cells and organisms. They have evolved to selfassemble, to serve as a protective shell for the viral genome during transfer, and to disassemble when entering a target cell. Disassembly during entry is a complex, multi-step process typically termed uncoating. Uncoating is triggered by multiple host-cell interactions. During cell entry, these interactions occur sequentially in different cellular compartments that the viruses pass through on their way to the site of replication. Here, we highlight the general principles of uncoating for two structurally related virus families, the polyoma- and papillomaviruses. Recent research indicates the use of different compartments and cellular interactions for uncoating despite their structural similarity.
to transmit the viral genomes from infected to uninfected cells or organisms. These particles are simple in content and structure and are composed of nucleic acids (RNA or DNA), proteins, and—for enveloped viruses—membrane lipids. Viral structural proteins assemble into capsids that protect the genomic information. These capsids are mostly spherical, often icosahedral structures, which are composed of many subunits of one or more proteins. Enveloped viruses have an additional lipid membrane displaying viral membrane glycoproteins. Despite their simplicity, virus particles are fascinating nanomachineries capable of selfassembling from limited structural components, of protecting the genome during transmission, and of mediating complex host-cell interactions during entry.
Keywords Papillomavirus Polyomavirus Virus entry Virus uncoating Virus structure
The assembly-uncoating paradox
Introduction Viruses are intracellular parasites that depend on the assistance of the host to replicate and to ‘live.’ In infected cells, new virus particles are built which serve as vehicles
C. Cerqueira M. Schelhaas Emmy-Noether Group ‘Virus Endocytosis’, Institutes of Molecular Virology and Medical Biochemistry, University of Mu¨nster, Mu¨nster, Germany M. Schelhaas (&) ZMBE, Institutes for Medical Biochemistry and Molecular Virology, University of Mu¨nster, Von-Esmarch-Str. 56, 48149 Mu¨nster, Germany e-mail:
[email protected]
A virus particle serves seemingly opposing functions [1]. For assembly and transmission, the different structural components associate within the nucleus or cytosol of an infected cell into a stable unit, which protect the viral genome from a hostile environment that features, for example, adverse chemical conditions and hydrolases. For successful entry into uninfected cells, the stable interactions must be reversed to release the viral genome into the cytosol or the nucleus for transcription and replication, a stepwise process termed uncoating. In this review, we discuss for two structurally related virus families, the polyoma- and papillomaviruses (PY and PV, respectively), how the dramatic change in virion stability occurs during transmission between two homologous environments. Despite their structural similarities, these viruses have evolved to employ different strategies for their uncoating program.
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PY and PV Both, PY and PV, are animal viruses with transforming potential (for an overview see [2, 3]). Most infections with human PY tend to cause mild diseases or to be asymptomatic in healthy individuals. However, the recently discovered Merkel cell polyomavirus (MCV) is connected to an aggressive malignancy of the skin, Merkel cell carcinoma [4]. More than 100 PV types are associated with a variety of infections that range from asymptomatic infections, over papilloma/wart formation to anogenital cancers [5]. Data on the structure and uncoating of PY have been mainly derived from Simian Virus 40 (SV40) and murine polyomavirus (mPY), but findings on the human viruses parallel the structural aspects and uncoating strategies seen for these model viruses (for recent reviews see [6–8]). The productive life cycle of PV requires differentiating human epidermal tissue allowing only limited virus production in vitro [9]. Thus, most structural information and insights into the uncoating program has been derived from viruslike particles (VLPs) and the so-called pseudoviruses. Pseudoviruses consist basically of VLPs that incorporate a reporter plasmid [10].
Structural similarities of polyomaand papillomaviruses PY and PV are small, non-enveloped double-stranded DNA viruses. Due to their overall similar structure, they were originally classified as a common virus family, the papovaviridae. The high divergence in genomic organization, in encoded genes and in the biology of their life cycles, has led to their classification as two separate virus families thereafter [11]. The major capsid proteins VP1 and L1 of PY and PV, respectively, form an icosahedral capsid (T = 7) built by 72 pentameric capsomers, from which 12 and 60 pentamers are pentavalently and hexavalently coordinated, respectively (Fig. 1; Table 1; [12–14]). Despite a lack of sequence similarity, VP1 and L1 both build the pentamer by forming a ring of five b-jellyroll domains. These are linked by interacting loops between the core unit of VP1 or L1. The core itself is composed of eight b-strands each [13, 15, 16]. For both, PY and PV, variable loops in the major capsid protein account for most of the neutralizing antibodies being induced [16–18]. Interpentameric links are provided by the C-terminal arm of VP1 or L1 that invades the neighboring pentamers [13, 15, 16, 19]. For PY, this interaction is stabilized by coordinating calcium ions [13, 15, 20–22]. For PV, stabilization by calcium ions seems to occur for bovine papillomavirus (BPV-1), whereas for HPV-11 and -16, calcium ions are most likely not required [23–25].
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Fig. 1 PV and PY structure. Electron micrograph of negatively stained virus particles, a HPV-16 pseudovirion and b SV40. Scale bars correspond to 50 nm. c Interpentamer connections according to the invading arm model [13, 19]. Triangles represent individual major capsid proteins that form a pentameric capsomer. Depicted is the hexavalent arrangement of capsomers
Interpentamer disulfide bonds further stabilize the capsids of PY and PV by either covalently linking the invading C-terminal arm to a neighboring pentamer (PV and SV40) [13, 15, 19, 22, 26–30] or by clamping it into place (mPY, [31]). Besides the major capsid protein, PY and PV encode for minor capsid proteins that are important for assembly and entry. In PY capsids, two minor capsid proteins are found: VP2 and the splice variant VP3 that lacks an N-terminal extension of about 120 amino acid residues including a myristylation site [32–34]. For PV, the single minor capsid protein is called L2. For the most part, VP2/VP3 and L2 are thought to locate within a central cavity of the capsomers [13, 15, 35–38]. Interaction of the minor capsid proteins with the capsomer occurs primarily by hydrophobic interactions [38–41]. Different to PY, where VP2/VP3 seem to be completely hidden inside the capsid [42], a stretch of
Med Microbiol Immunol Table 1 Overview of the main structural characteristics of PY and PV
Listed are the icosahedral isometry, structural proteins, capsomer arrangement, and intercapsomeric contacts stabilizing the capsomer
Polyomaviruses
Papillomaviruses
Reference [12–16]
Isometry
T = 7 icosahedral
T = 7 icosahedral
Capsomer
Pentamer of VP1
Pentamer of L1
[13, 15, 35, 132, 133]
Viral structural proteins
Major: VP1
Major: L1
[14, 35, 36]
Minor: VP2/VP3
Minor: L2
Stabilization of capsomer contacts
VP1 C-terminal arms invade neighboring capsomers
L1 C-terminal arms invade neighboring capsomers
Calcium binding
Interchain disulfide bonds
[13, 15, 16, 19–22, 26–30]
Interchain disulfide bonds Interaction between capsid proteins
Hydrophobic interactions
about 60 amino acids (aa) close to the N-terminus of L2 is exposed on the capsid surface of PV (e.g., aa 60–120 in the case of BPV-1) [43–45]. However, the extreme N-terminus is thought to fold back into the capsid lumen [46, 47]. Both viruses assemble in the nucleus of infected cells, although—at least for PY—pentamers may be formed already in the cytoplasm [48]. The minor capsid proteins help to incorporate the viral DNA [49, 50]. The formation of disulfide bonds is unlikely to occur in the nucleus due to its reducing environment. Rather, particles mature after cell lysis when the virions are exposed to the oxidizing cell exterior. For PV, it has been shown that maturation of PsV after cell lysis increases the resistance of the virus to proteases [51], whereas in vivo it may be helped by a redox gradient within epidermal tissue [52]. As summarized in Table 1, PY and PV resemble each other in most of the structural elements that stabilize the viral capsids despite a lack in sequence similarity. Virion stability is in principle conferred by strong hydrophobic interaction of the major capsid proteins within a pentamer, by interpentameric links through invading C-terminal arms of neighboring pentamers, and by interchain disulfide bond formation that occurs by maturation. At least some of these stabilizing features need to be reversed for uncoating.
Endoplasmic reticulum-associated machineries facilitate the uncoating of polyomaviruses For binding and internalization, most PY can use gangliosides, that is, glycosphingolipids containing one or more sialic acids [53–57], see also [6, 7, 58]. Although viral interactions with sialic acids on proteins are possible and may be functional, at least for mPY this interaction is futile by restriction of intracellular sorting events that prevent trafficking to infectious compartments [59]. In contrast, JC virus uses a sialic acid-based glycan, LSTc, as receptor, but requires in addition the serotonin receptor 5-HT2A [60–62]. MCV also seems to use two receptor
Hydrophobic interactions
[38–41]
molecules, it binds to heparan sulfate proteoglycans (HSPGs) but may engage sialic acid containing molecules in a second step [63]. Binding affinities between viruses and sialic acids are typically low, but highly specific for a given virus (discussed in detail by [58]). The available x-ray crystallographic data suggest that binding occurs within small contact areas and that they do not induce any conformational changes in the virion [31, 58, 64, 65]. Preincubation of mPY with oligosaccharide receptor fragments increases binding and infectivity, and confers protease resistance of the virion on cells. This has been previously interpreted as induction of a conformational change [66]. Given the structural data, alternative interpretations may be that protease consensus sites are covered by the receptor fragments, or that less specific binding to decoy receptors is blocked, whereas binding to gangliosides may be possible. In any case, the structure of polyomaviruses seems to remain largely unchanged prior to internalization and is thus most likely not activated for uncoating. Internalization of PY into cells occurs mostly by caveolar/lipid raft endocytosis [42, 67–70]. The exception is JC virus that is internalized by clathrin-mediated endocytosis [71, 72]. PY are routed through endosomal compartments and are eventually delivered to the endoplasmic reticulum (ER), which makes them unusual among other viruses [71, 73–76]. For mPY, the ganglioside receptor GD1a mediates sorting to the ER [75], and it is likely that sorting to the ER generally depends on the receptor usage. During endosomal passage, PY encounter a low pH and proteases. For many viruses, conformational changes and proteolytic shedding of virion proteins are induced in endosomes for partial uncoating [77]. Neutralization of the low endosomal pH by lysosomotropic agents typically blocks infection, which has also been observed for PY [73, 75, 78]. However, it is unclear, whether a low pH induces conformational changes in the capsids of most PY. For mPY, a conformational change in the viral particle has been suggested [75]. In contrast, for SV40, neutralization interferes
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with the endocytic internalization of particles [73], which suggest that the effects observed by lysosomotropic agents may be related to trafficking defects rather than changes in virion structure. Likewise, proteolysis of viral components in endosomal compartments has not been observed [76, 78]. Taken together, it is generally assumed that PY particles arrive in the ER largely unmodified in their structure and that uncoating is in fact initiated in the ER. Most detailed information on the interactions that facilitate uncoating of PY within the ER is derived from mPY and SV40. The interactions largely resemble the behavior of certain bacterial toxins in that they pose as misfolded proteins to engage the ER protein folding and quality control machinery and hijack the ER-associated degradation (ERAD) machinery (see also [79]). Upon arrival in the ER, SV40 is released into the lumen [80]. For SV40, the protein disulfide isomerase (PDI) family member ERp57 isomerases the C9–C9 disulfide bond, which links the vertex to the adjacent pentamers, to a C9–C104 intrachain disulfide bond [76]. In effect, the vertex pentamer interactions with the rest of the capsid are destabilized. Similar observations have been made for mPY and BK virus [78, 81, 82]. In addition, multiple ER chaperones are required for mPY or SV40 infection, that is, ERp29 or PDI, BiP, BAP31, and DNAJ family members, respectively [76, 83–86]. They seem to help exposing the minor capsid proteins VP2/VP3 [42, 83–88]. In addition, they may mediate recognition of the viral particles by the quality control or ERAD machinery. Exposure of VP2 seems to lead to binding of and integration into the ER membrane, an interaction, which has the ability to perforate the membranes [85, 88]. These events are consistent with the initiation of viral penetration into the cytosol. Whether membrane insertion of VP2 alone allows membrane penetration, is unclear. SV40 is translocated into the cytosol as a largely intact structure [80], which may explain the involvement of ERAD factors [76, 78, 83, 89]. Transfer of a large structure across membranes requires an enormous amount of energy. Derlin, a retrotranslocation channel protein, has been implicated in PY infection [80, 89–91]. Interaction with derlin may facilitate a potential recruitment of cytosolic ERAD factors that could help to extract membrane bound PY particles. Alternatively, derlins might form channels large enough for a transfer. In the cytosol, the destabilized PY capsids disassemble, further rendering the DNA accessible for detection [80, 87]. How this occurs mechanistically is not clear. It has been proposed that cytosolic disassembly may be facilitated by a lower calcium concentration [76]. In addition, interactions with Hsp70 chaperones may contribute to this process [92, 93]. To date it is unknown, which remaining viral structure would be imported into the nucleus to initiate infection.
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Stepwise disassembly of PV in different cell compartments Many cell biological characteristics of PV entry have been identified during the last decade. A number of cellular co-factors facilitating endocytic uptake and initial infection has been identified [94]. Here, we will focus on the interactions that may mediate uncoating of PV. PV can bind directly to cells or to extracellular matrix (ECM) components [95–98]. Binding to tissue culture cells requires heparan sulfate proteoglycans (HPSG) for various types [99–104]. HPV-11 can bind to glypicans and syndecans for infection suggesting that binding may be independent of a specific proteoglycan [102]. However, since syndecan-1 is very abundant in keratinocytes or wounded epidermal tissue, it may be the primary interaction partner for cell binding during infection as it has been proposed recently for HPV-16 [105]. HPV-11 binds ECM secreted by keratinocytes through interactions with laminin-332, whereas HPV-16 and -45 bind ECM partially via heparan sulfates and laminin-332 [95–98]. However, data from a mouse vaginal challenge model suggest that binding of HSPGs may be the exclusive mode of interaction with basement membranes in vivo [103, 106]. Early studies showed that HPV-33 infection becomes resistant to competition by heparin after binding, which may be due to binding of a secondary receptor and/or a conformational change in the virion [101]. The existence of a putative secondary receptor for PV has been supported by experiments using heparin binding drugs that prevent transfer from HSPGs to the elusive receptor and that block infection [98]. Although most PV seem to require HSPGs for binding, this interaction may not be facultative for all subtypes as shown for HPV-31 and HPV-5 in tissue culture [107, 108]. Interestingly, in the mouse model HPV-5 and 31 bind HSPGs on the basement membrane [103]. That antibodies recognize and neutralize infection differentially before and after cell attachment, supports the notion of changes in the conformation of HPV-33 on the cell surface [109]. For HPV-16, these structural changes involve the action of a cell surface-associated peptidylprolyl isomerase, cyclophilin B, which appears to expose the N-terminus of L2 that is originally buried within the capsid structure [110, 111]. Furin, a cellular proprotein convertase, cleaves a conserved consensus site within the exposed C-terminus of L2 [112]. Furin-precleaved virus can infect cells independently of attachment to HSPGs, which further supports the use of a secondary receptor [113]. Both interactions, with furin and with cyclophilin B, are required for infection. Besides allowing transfer or binding of a secondary receptor, they constitute most likely the first changes toward uncoating. For a more detailed discussion
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of cell surface-associated conformational changes, see ([6] and [94]). Infectious internalization occurs slowly and asynchronously, which suggests that one of the conformational changes on the cell surface/ECM and/or the subsequent transfer to the secondary receptor is rate limiting [114]. Endocytosis of PV has been attributed to many different mechanisms [115–120]. For HPV-16 entry, a recent study analysed comprehensively the contributions of most key factors involved in the endocytic pathways known to date [114]. Together with a previous study, the cumulative evidence indicates that HPV-16 entry occurs by a novel clathrin-, caveolin-, lipid raft-independent, but actindependent endocytic pathway that may involve tetraspanin microdomains [114, 121]. This pathway has not been described in detail in the existing literature before, which may explain the attribution of PV entry to various different endocytic mechanisms previously. After endocytosis, all PV types that have been tested require a low endosomal pH for infection which suggests viral passage through the endosomal pathway [114, 117, 119, 122–124]. PV appear to spend a protracted time in endosomal compartments, since HPV-16 is sensitive to pH neutralization for two to three hours after infectious internalization [114]. Viral particles accumulate in late endosomes/lysosomes [112, 114, 119, 125–127], which are able to support infection [114]. Unlike PY, PV localization to the ER has not been observed. Like for many other viruses, it has been suggested that low pH or pH-dependent proteases facilitate uncoating and/or membrane penetration by structurally altering the viral capsid. In fact, structural changes of PV virions in endosomal compartments have been observed though not causally linked to a defined compartment: (1) exposure of an epitope that is buried in the viral capsid (HPV-16, -33, [121, 128]); (2) exposure of the L2 C-terminus [46, 112, 125, 126, 129] and the viral pseudogenome [46, 112, 125, 126, 130]. It is interesting to note that while L2 becomes progressively more accessible, epitopes against L1 seem to disappear consistent with major structural alterations and/or degradation of L1 [112, 126]. A number of factors has been recently implicated to assist in the later stages of PV entry (for more information, see [94]). How several of these proteins contribute mechanistically to uncoating, however, remains to be largely speculative. The role of endosomal proteases has been addressed by two studies using, for example, inhibitors of cathepsins [46, 124]. Since the inhibitors do not affect infection or only to a minor extend, it seems unlikely that cathepsins play a major role in uncoating. Addressing the potential reversal of stabilizing disulfides in interpentameric contacts, Campos et al. [130] suggested an involvement of PDI family members analogous to PY.
Although PDIs reside mostly in the ER, the interaction was hypothesized to occur in endosomal compartments. Unfortunately, clear conclusions are hampered by the fact that PDIs are not specifically inhibited by bacitracin [131], the main inhibitor used in the PV entry study [130]. So it remains unclear, how the stabilizing interpentameric contacts are reversed. Interestingly, cyclophilins are able to release L1 pentamers from L2 in a low pH-dependent manner in vitro [122]. Further, inhibition or knockdown of cyclophilins increases the amount of L2 signals colocalizing with L1 signal, which indicates a failed separation of L1 and L2 [122]. Thus, cyclophilins appear to be chaperones that assist in shedding of pentamers from the viral structure. Perturbation of the intramembrane protease c-secretase affects nuclear localization of pseudogenomes but not intracellular trafficking of the virus, or L2 and pseudogenome exposure [125]. Hence, a role of c-secretase in membrane penetration has been suggested. How c-secretase actually facilitates this process remains to be investigated in more detail. A membrane destabilizing peptide in L2 is hypothesized to facilitate membrane penetration by insertion into membranes [132]. Translocation of the viral histone-genome complex through a membrane or more so organelle lysis would require a large amount of energy. Thus, it seems unlikely that insertion into the membrane of the limited number of L2 molecules present in a virion would be sufficient to provide this energy. This may suggest the involvement of further host factors to assist in membrane penetration. An interaction of sorting nexin 17 with L2 after the putative membrane insertion may retain the remnant virion in a compartment that favors penetration [126]. In the nucleus, only L2 and the viral genome has been detected [112]. Whether L2 and the histone complexes are sufficient to protect the viral genome through their passage in the cytsosol, is an open question. In summary, PV appear to initiate the uncoating process by a series of extracellular conformational changes in the virion. This is followed by further uncoating events in endosomal compartments that may be linked to membrane penetration. In which form the virus remnant structure is translocated, and whether further changes in the cytosol occur has not been investigated so far.
Summary and perspectives PY and PV have evolved to form capsids that exhibit a striking structural similarity despite a lack of significant sequence similarity between the respective structural proteins. Both viruses commonly use structural modifications of their capsid which occur through interactions with host-cell factors during entry into host cells for uncoating. Although many details in the uncoating process of PY and PV or more
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Med Microbiol Immunol Table 2 Overview of the main structural changes during PY uncoating Structural change
PY
Cellular co-factor
Location
Reference
Conformational change
mPY
Low pH
Endolysosomes
[75]
Isomerization of disulfide bonds of VP1 pentamer
SV40, mPY
PDI family members
ER
[76, 81, 82]
Conformational change: exposure of C-terminal arm of VP1 Conformational change: VP2/VP3 exposure
mPY
ERp29
ER
[85]
SV40, mPY
ErP29, PDI, BiP, BAP31, DNA J family
ER
[42, 76, 83–88]
Conformational change: genome exposure
SV40
Calcium?
Cytosol
[76, 87]
Capsomer shedding
SV40, mPY
Hsp70?
Cytosol
[80, 92, 93]
Listed are the major examples for changes in viral structure during cell entry which have been shown or hypothesized in the references provided. Given are also the detected or presumed locations of the change within the cell. The changes are ordered such that they reflect particles on their way toward the site of replication; ? proposed
Table 3 Overview of the main structural changes during PV uncoating Structural change
HPV type
Cellular co-factor
Location
Reference
Conformational change: heparin resistance
33
?
Cell surface
[101]
Conformational change: H33.J3 epitope exposure (aa 51–58)
33
?
Cell surface
[109, 135]
Conformational change: exposure of L2 N-terminus
16
Cyclophilin B
Cell surface/basement membrane
[110, 111]
L2 N-terminus cleavage
16, BPV
Furin
Cell surface/basement membrane
[46, 104, 113]
Conformational change: L1-7 epitope exposure (aa 329–339)
16
Low pH
Endosomes
[121, 128]
Genome exposure
16, BPV
Low pH
Endosomes
[46, 112, 125, 126, 130]
Capsomer shedding L1–L2 separation
16
Cyclophilins
Endosomes
[112, 122]
Membrane penetration
16
c-secretase
Endosomes
[125]
Listed are the major examples for changes in viral structure during cell entry which have been shown or hypothesized in the references provided. Given are also the detected or presumed locations of the change within the cell. The changes are ordered such that they reflect particles on their way toward the site of replication; ? unknown
so of virus types are still lacking, it has become apparent over the past decade that PY and PV use different sets of cellular compartments, interaction partners, and triggers to facilitate the stepwise process of uncoating (for overview, see Table 2, 3). PY use mostly gangliosides for transport to the ER. In contrast, PV are transported to late endosomal/ lysosomal compartments. The major structural changes in PY capsid seem to be initiated in the ER, whereas for PV uncoating most likely starts with changes initiated extracellularly. PY appear to shed capsomers in the cytosol, whereas for PV this may already occur within endosomes. The theme of divergent uncoating principles between PY and PV has become clear, but there are several key questions still unanswered. For example, how are the stabilizing interpentameric contacts in PV weakened? How are the viral genomes structurally protected until they enter
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the nucleus? Are there cellular factors associated with them, and if so, which ones? How are they shed for transcriptional activation? We can also expect that different viruses from the same family utilize different but analogous host-cell factors such as ER chaperones for PY to achieve a similar outcome. Hence, more efforts are required to fully understand the uncoating process for the different viruses. Acknowledgments The authors would like to acknowledge the help of Dr. R. Mancini in acquisition of electron micrographs. We apologize to all those great individuals who have advanced the field of polyoma- and papillomavirus structure and entry, and who were not mentioned in the manuscript due to space limitations. MS and CC were supported by the German Science Foundation (DFG, Emmy-Noether grant SCHE 1552/2-1) and by the Portuguese Foundation for Science and Technology (PhD grant SFRH/BD/45921/2008), respectively.
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