Nipah Virus Entry and Egress from Polarized Epithelial Cells

Lamp, Boris; Dietzel, Erik; Kolesnikova, Larissa; Sauerhering, Lucie; Erbar, Stephanie; Weingartl, Hana M.; Maisner, Andrea

doi:10.1128/jvi.02696-12

Cited by 50 publications

(60 citation statements)

References 70 publications

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“…Scale bar: 20 µm. Co-transfection with NiV-F and NiV-G constructs resulted in the frequent appearance of fused neurons (typically 2–3 cells) consistent with the role of these glycoproteins in cell-to-cell fusion [15], [26], [27]. Only isolated neurons co-transfected with NiV-F and NiV-G, showing unaltered distribution of MAP2 and ANK-G markers, were selected for quantitative analysis of polarity of the two glycoproteins (Table 1).…”

Section: Resultsmentioning

confidence: 97%

Co-assembly of Viral Envelope Glycoproteins Regulates Their Polarized Sorting in Neurons

et al. 2014

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Newly synthesized envelope glycoproteins of neuroinvasive viruses can be sorted in a polarized manner to the somatodendritic and/or axonal domains of neurons. Although critical for transneuronal spread of viruses, the molecular determinants and interregulation of this process are largely unknown. We studied the polarized sorting of the attachment (NiV-G) and fusion (NiV-F) glycoproteins of Nipah virus (NiV), a paramyxovirus that causes fatal human encephalitis, in rat hippocampal neurons. When expressed individually, NiV-G exhibited a non-polarized distribution, whereas NiV-F was specifically sorted to the somatodendritic domain. Polarized sorting of NiV-F was dependent on interaction of tyrosine-based signals in its cytosolic tail with the clathrin adaptor complex AP-1. Co-expression of NiV-G with NiV-F abolished somatodendritic sorting of NiV-F due to incorporation of NiV-G•NiV-F complexes into axonal transport carriers. We propose that faster biosynthetic transport of unassembled NiV-F allows for its proteolytic activation in the somatodendritic domain prior to association with NiV-G and axonal delivery of NiV-G•NiV-F complexes. Our study reveals how interactions of viral glycoproteins with the host's transport machinery and between themselves regulate their polarized sorting in neurons.

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Section: Resultsmentioning

confidence: 97%

Co-assembly of Viral Envelope Glycoproteins Regulates Their Polarized Sorting in Neurons

et al. 2014

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“…In the viral context, however, both glycoproteins are expressed in a more apical fashion. This redistribution is assumed to be caused by the NiV M that is selectively targeted to the apical surface of polarized cells (14,41,42). This M-driven apical accumulation of all viral components is thought to ensure efficient apical NiV budding while downregulating F/G-dependent lateral cell-to-cell fusion kinetics within the polarized cell monolayer.…”

Section: Discussionmentioning

confidence: 99%

“…Though the detailed role varies between different viruses, paramyxoviral M proteins are generally considered the main drivers of assembly (11). Supporting the idea of a critical role in virus particle formation and budding, NiV M protein forms virus-like particles (VLPs) when expressed on its own (12,13), and it drives apical assembly and budding of NiV virions in polarized epithelial cells (14). Trafficking of NiV M is a complex process involving transit through the nucleus (15)(16)(17)(18), despite replication occurring exclusively in the cytoplasm.…”

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confidence: 99%

Nipah Virus Matrix Protein Influences Fusogenicity and Is Essential for Particle Infectivity and Stability

Dietzel

Kolesnikova

Sawatsky

et al. 2016

J Virol

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Nipah virus (NiV) causes fatal encephalitic infections in humans. To characterize the role of the matrix (M) protein in the viral life cycle, we generated a reverse genetics system based on NiV strain Malaysia. Using an enhanced green fluorescent protein (eGFP)-expressing M protein-deleted NiV, we observed a slightly increased cell-cell fusion, slow replication kinetics, and significantly reduced peak titers compared to the parental virus. While increased amounts of viral proteins were found in the supernatant of cells infected with M-deleted NiV, the infectivity-to-particle ratio was more than 100-fold reduced, and the particles were less thermostable and of more irregular morphology. Taken together, our data demonstrate that the M protein is not absolutely required for the production of cell-free NiV but is necessary for proper assembly and release of stable infectious NiV particles. IMPORTANCEHenipaviruses cause a severe disease with high mortality in human patients. Therefore, these viruses can be studied only in biosafety level 4 (BSL-4) laboratories, making it more challenging to characterize their life cycle. Here we investigated the role of the Nipah virus matrix protein in virus-mediated cell-cell fusion and in the formation and release of newly produced particles. We found that even though low levels of infectious viruses are produced in the absence of the matrix protein, it is required for the release of highly infectious and stable particles. Fusogenicity of matrixless viruses was slightly enhanced, further demonstrating the critical role of this protein in different steps of Nipah virus spread.

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“…While morbillivirus F and H proteins associate very early during biosynthesis (Plemper et al, 2001), F also forms VLPs when co-expressed with M (Cathomen et al, 1998a;Pohl et al, 2007), and recombinant MeVs with partially deleted cytoplasmic tails were viable (Cathomen et al, 1998b), it remains unclear which glycoprotein interacts more strongly with the homologous M protein to drive morbillivirus particle formation. In contrast, henipavirus glycoproteins are transported independently and only associate transiently on the cell surface (Lamp et al, 2013;Whitman & Dutch, 2007;Whitman et al, 2009). Recent studies on VLP formation by the NiV M protein have demonstrated that henipavirus glycoprotein incorporation is a haphazard process, where at least half of the VLPs produced have no surface glycoproteins (Landowski et al, 2014).…”

Section: Incorporation Of Niv G Into Vlps Is Non-specificmentioning

confidence: 99%

Morbillivirus and henipavirus attachment protein cytoplasmic domains differently affect protein expression, fusion support and particle assembly

Sawatsky

Bente

Czub

et al. 2016

Journal of General Virology

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The amino-terminal cytoplasmic domains of paramyxovirus attachment glycoproteins include trafficking signals that influence protein processing and cell surface expression. To characterize the role of the cytoplasmic domain in protein expression, fusion support and particle assembly in more detail, we constructed chimeric Nipah virus (NiV) glycoprotein (G) and canine distemper virus (CDV) haemagglutinin (H) proteins carrying the respective heterologous cytoplasmic domain, as well as a series of mutants with progressive deletions in this domain. CDV H retained fusion function and was normally expressed on the cell surface with a heterologous cytoplasmic domain, while the expression and fusion support of NiV G was dramatically decreased when its cytoplasmic domain was replaced with that of CDV H. The cell surface expression and fusion support functions of CDV H were relatively insensitive to cytoplasmic domain deletions, while short deletions in the corresponding region of NiV G dramatically decreased both. In addition, the first 10 residues of the CDV H cytoplasmic domain strongly influence its incorporation into virus-like particles formed by the CDV matrix (M) protein, while the co-expression of NiV M with NiV G had no significant effect on incorporation of G into particles. The cytoplasmic domains of both the CDV H and NiV G proteins thus contribute differently to the virus life cycle.

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Nipah Virus Entry and Egress from Polarized Epithelial Cells

Cited by 50 publications

References 70 publications

Co-assembly of Viral Envelope Glycoproteins Regulates Their Polarized Sorting in Neurons

Co-assembly of Viral Envelope Glycoproteins Regulates Their Polarized Sorting in Neurons

Nipah Virus Matrix Protein Influences Fusogenicity and Is Essential for Particle Infectivity and Stability

Morbillivirus and henipavirus attachment protein cytoplasmic domains differently affect protein expression, fusion support and particle assembly

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