Phosphorylation of Marburg virus matrix protein VP40 triggers assembly of nucleocapsids with the viral envelope at the plasma membrane

Kolesnikova, Larissa; Mittler, Eva; Schudt, Gordian; Shams‐Eldin, Hosam; Becker, Stephan

doi:10.1111/j.1462-5822.2011.01709.x

Cited by 40 publications

(44 citation statements)

References 47 publications

(77 reference statements)

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“…Similarly, IQGAP1, which is involved in cytoskeletal remodeling during cell migration and the formation of filopodia, interacts with ebolavirus VP40 and facilitates the release of virus-like particles [88]. Recently, phosphorylation of VP40 was shown to be essential for efficient assembly and budding [89,90]. In addition, it has been shown that NP and VP40 detected in virus particles are phosphorylated [91,92].…”

Section: Assembly/egressmentioning

confidence: 99%

Host Cell Factors Involved in Filovirus Infection

Kajihara

Takada

2015

Curr Trop Med Rep

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Filoviruses (ebolaviruses and marburgviruses) cause severe hemorrhagic fever in humans and nonhuman primates with high mortality rates of up to 90 %. The latest epidemic of Ebola virus disease in Western African countries has underscored the urgent need for effective prophylactic and therapeutic interventions for this deadly infectious disease. However, neither approved prophylactics nor therapeutics are currently available for filovirus diseases. Recent studies have been unveiling the molecular mechanisms underlying the filovirus lifecycle, including cellular entry, egress, and the evasion from host immunity, suggesting possibilities to develop effective pan-filovirus drugs.

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Section: Assembly/egressmentioning

confidence: 99%

Host Cell Factors Involved in Filovirus Infection

Kajihara

Takada

2015

Curr Trop Med Rep

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“…[92][93][94] Although VP35 is the major polymerase cofactor in ebola virus, no clear evidence con¯rms that it can be phosphorylated. 57,[85][86][87] Therefore, similar replication-transcription regulatory function, if probable, could only be carried out by VP30, which is the closest counterpart in ebola virus of phosphorylation protein P in this context. Direct interactions of VP30 with NP, VP35, L and RNA have all been identi¯ed, and a VP30 mediatory function of viral replication and transcription through phosphorylation shift has also been observed.…”

Section: Modulation Of Np Conformationmentioning

confidence: 99%

“…84 The phosphorylation state of VP30 could control NP-VP35-L complex functions. 57,77,[85][86][87] Biedenkopf et al 74 propose that a trimeric complex of VP30, VP35 and L is involved in the regulation of RNA replication and transcription. In particular, this trimeric complex promotes transcription of viral RNA when VP30 is in the nonphosphorylated state, while phosphorylation of VP30, inducing release of VP30 from the trimeric complex, results in shift of the status of viral RNA synthesis from transcription to viral replication (Fig.…”

Section: Modulation Of Np Conformationmentioning

confidence: 99%

“…56 VP40 is critical in the recruitment of NC and GP to plasma membrane for viral assembly and budding. 57,58 Generally, six residues were identi¯ed in charge variations of the NP C-terminal domain, three negatively charged residues, D681, D707 and D729, in Reston NP and the other three negatively charged residues, E695, D708 and D716, in Zaire NP (Figs. 3(c) and 3(d)).…”

Section: The E®ects Of Variations In the Np C-terminal Domain On The mentioning

confidence: 99%

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Interplay Among Constitutes of Ebola Virus: Nucleoprotein, Polymerase L, Viral Proteins

Zhang

Ping

et al. 2017

Biophys. Rev. Lett.

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Ebola virus is a highly lethal¯lovirus, claimed thousands of people in its recent outbreak. Seven viral proteins constitute ebola viral structure, and four of them (nucleoprotein (NP), polymerase L, VP35 and VP30) participate majorly in viral replication and transcription. We have elucidated a conformation change of NP cleft by VP35 NP-binding protein domains through superimposing two experimental NP structure images and discussed the function of this conformation change in the replication and transcription with polymerase complex (L, VP35 and VP30). The important roles of VP30 in viral RNA synthesis have also been discussed. A \tapping" model has been proposed in this paper for a better understanding of the interplay among the four viral proteins (NP, polymerase L, VP35 and VP30). Moreover, we have pinpointed some key residue changes on NP (both NP N-and C-terminal) and L between Reston and Zaire by computational studies. Together, this paper provides a description of interactions among ebola viral proteins (NP, L, VP35, VP30 and VP40) in viral replication and transcription, and sheds light on the complex system of viral reproduction.

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“…HEK293 cells were used for flotation, reporter gene, VLP, and iVLP assays because of their high transfection efficiency. Huh-7 and VeroE6 cells, which are more susceptible to infection with MARV than HEK293 cells (21,22), were used for virus titration and analysis of viral growth kinetics and for immunofluorescence analysis.…”

Section: Cellsmentioning

confidence: 99%

A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner

Koehler

Kolesnikova

Welzel

et al. 2016

J Virol

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Marburg virus (MARV) induces severe hemorrhagic fever in humans and nonhuman primates but only transient nonlethal disease in rodents. However, sequential passages of MARV in rodents boosts infection leading to lethal disease. Guinea pig-adapted MARV contains one mutation in the viral matrix protein VP40 at position 184 (VP40 D184N ). The contribution of the D184N mutation to the efficacy of replication in a new host is unknown. In the present study, we demonstrated that recombinant MARV containing the D184N mutation in VP40 [rMARV VP40(D184N) ] grew to higher titers than wild-type recombinant MARV (rMARV WT ) in guinea pig cells. Moreover, rMARV VP40(D184N) displayed higher infectivity in guinea pig cells. Comparative analysis of VP40 functions indicated that neither the interferon (IFN)-antagonistic function nor the membrane binding capabilities of VP40 were affected by the D184N mutation. However, the production of VP40-induced virus-like particles (VLPs) and the recruitment of other viral proteins to the budding site was improved by the D184N mutation in guinea pig cells, which resulted in the higher infectivity of VP40 D184N -induced infectious VLPs (iVLPs) compared to that of VP40-induced iVLPs. In addition, the function of VP40 in suppressing viral RNA synthesis was influenced by the D184N mutation specifically in guinea pig cells, thus allowing greater rates of transcription and replication. Our results showed that the improved viral fitness of rMARV VP40(D184N) in guinea pig cells was due to the better viral assembly function of VP40 D184N and its lower inhibitory effect on viral transcription and replication rather than modulation of the VP40-mediated suppression of IFN signaling. IMPORTANCEThe increased virulence achieved by virus passaging in a new host was accompanied by mutations in the viral genome. Analyzing how these mutations affect the functions of viral proteins and the ability of the virus to grow within new host cells helps in the understanding of the molecular mechanisms increasing virulence. Using a reverse genetics approach, we demonstrated that a single mutation in MARV VP40 detected in a guinea pig-adapted MARV provided a replicative advantage of rMARV VP40(D184N) in guinea pig cells. Our studies show that this replicative advantage of rMARV VP40 D184N was based on the improved functions of VP40 in iVLP assembly and in the regulation of transcription and replication rather than on the ability of VP40 to combat the host innate immunity. F iloviruses, including Ebolaviruses (EBOV) and Marburg virus (MARV), are enveloped, nonsegmented, negative-strand RNA viruses (1). These viruses are known to cause severe fevers in humans and nonhuman primates, with case fatality rates of up to 90% (2). Although several antivirals and vaccines currently are being tested in clinical studies, none of them are licensed for human use. Therefore, work with filoviruses is restricted to biosafety level 4 (BSL-4) facilities. The recent EBOV outbreak in Guinea, Sierra Leone, and Liberia demonstrated the ...

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Phosphorylation of Marburg virus matrix protein VP40 triggers assembly of nucleocapsids with the viral envelope at the plasma membrane

Cited by 40 publications

References 47 publications

Host Cell Factors Involved in Filovirus Infection

Host Cell Factors Involved in Filovirus Infection

Interplay Among Constitutes of Ebola Virus: Nucleoprotein, Polymerase L, Viral Proteins

A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner

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