Ebola Virus NP Binding to Host Protein Phosphatase-1 Regulates  Capsid Formation

Ahmad, Asrar; Tigabu, Bersabeh; Ivanov, Andrey; Jerebtsova, Marina; Ammosova, Tatiana; Ramanathan, P.; Kumari, Namita; Brantner, Christine A.; Pietzsch, Colette; Abdullah, G.; Popratiloff, Anastas; Widen, Steve G.; Bukreyev, Alexander; Nekhai, Sergeï

doi:10.21203/rs.3.rs-2963943/v1

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…The interaction between EBOV infection is actually a complex conflict between the host and the virus. On the one hand, EBOV increases its replication, evades the host immune response and accelerates disease progression by interacting with host factors including Protein Phosphatase 1 (PP1) [ 29 ], SET and MYND domain-containing protein (SMYD3) [ 30 ]; and carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) [ 31 ]. On the other hand, the host restricts or even inhibits the replication of EBOV by interacting with the virus [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

RNA binding motif 4 inhibits the replication of ebolavirus by directly targeting 3′-leader region of genomic RNA

Fan,

Wang,

Huang

et al. 2024

Emerging Microbes & Infections

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Ebola virus (EBOV) belongs to Filoviridae family possessing single-stranded negative-sense RNA genome, which is a serious threat to human health. Nowadays, no therapeutics have been proven to be successful in efficiently decreasing the mortality rate. RNA binding proteins (RBPs) are reported to participate in maintaining cell integrity and regulation of viral replication. However, little is known about whether and how RBPs participate in regulating the life cycle of EBOV. In our study, we found that RNA binding motif protein 4 (RBM4) inhibited the replication of EBOV in HEK293T and Huh-7 cells by suppressing viral mRNA production. Such inhibition resulted from the direct interaction between the RRM1 domain of RBM4 and the “CU” enrichment elements located in the PE1 and TSS of the 3′-leader region within the viral genome. Simultaneously, RBM4 could upregulate the expression of some cytokines involved in the host innate immune responses to synergistically exert its antiviral function. The findings therefore suggest that RBM4 might serve as a novel target of anti-EBOV strategy.

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Section: Discussionmentioning

confidence: 99%

RNA binding motif 4 inhibits the replication of ebolavirus by directly targeting 3′-leader region of genomic RNA

Fan,

Wang,

Huang

et al. 2024

Emerging Microbes & Infections

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Hippo signaling pathway regulates Ebola virus transcription and egress

Liang,

Djurkovic,

Leavitt

et al. 2024

Nat Commun

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Filovirus-host interactions play important roles in all stages of the virus lifecycle. Here, we identify LATS1/2 kinases and YAP, key components of the Hippo pathway, as critical regulators of EBOV transcription and egress. Specifically, we find that when YAP is phosphorylated by LATS1/2, it localizes to the cytoplasm (Hippo “ON”) where it sequesters VP40 to prevent egress. In contrast, when the Hippo pathway is “OFF”, unphosphorylated YAP translocates to the nucleus where it transcriptionally activates host genes and promotes viral egress. Our data reveal that LATS2 indirectly modulates filoviral VP40-mediated egress through phosphorylation of AMOTp130, a positive regulator of viral egress, but more surprisingly that LATS1/2 kinases directly modulate EBOV transcription by phosphorylating VP30, an essential regulator of viral transcription. In sum, our findings highlight the potential to exploit the Hippo pathway/filovirus axis for the development of host-oriented countermeasures targeting EBOV and related filoviruses.

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The cellular protein phosphatase 2A is a crucial host factor for Marburg virus transcription

von Creytz,

Rohde,

Biedenkopf

2024

J Virol

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Little is known regarding the molecular mechanisms that highly pathogenic Marburg virus (MARV) utilizes to transcribe and replicate its genome. Previous studies assumed that dephosphorylation of the filoviral transcription factor VP30 supports transcription, while phosphorylated VP30 reduces transcription. Here, we focused on the role of the host protein phosphatase 2A (PP2A) for VP30 dephosphorylation and promotion of viral transcription. We could show that MARV NP interacts with the subunit B56 of PP2A, as previously shown for the Ebola virus, and that this interaction is important for MARV transcription activity. Inhibition of the interaction between PP2A and NP either by mutating the B56 binding motif encoded on NP, or the use of a PP2A inhibitor, induced VP30 hyperphosphorylation, and as a consequence a decrease of MARV transcription as well as viral growth. These results suggest that NP plays a key role in the dephosphorylation of VP30 by recruiting PP2A. Generation of recombinant (rec) MARV lacking the PP2A-B56 interaction motif on NP was not possible suggesting an essential role of PP2A-mediated VP30 dephosphorylation for the MARV replication cycle. Likewise, we were not able to generate recMARV containing VP30 phosphomimetic mutants indicating that dynamic cycles of VP30 de- and rephosphorylation are a prerequisite for an efficient viral life cycle. As the specific binding motifs of PP2A-B56 and VP30 within NP are highly conserved among the filoviral family, our data suggest a conserved mechanism for filovirus VP30 dephosphorylation by PP2A, revealing the host factor PP2A as a promising target for pan-filoviral therapies. IMPORTANCE Our study elucidates the crucial role of host protein phosphatase 2A (PP2A) in Marburg virus (MARV) transcription. The regulatory subunit B56 of PP2A facilitates VP30 dephosphorylation, and hence transcription activation, via binding to NP. Our results, together with previous data, reveal a conserved mechanism of filovirus VP30 dephosphorylation by host factor PP2A at the NP interface and provide novel insights into potential pan-filovirus therapies.

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Ebola Virus NP Binding to Host Protein Phosphatase-1 Regulates Capsid Formation

Cited by 3 publications

References 41 publications

RNA binding motif 4 inhibits the replication of ebolavirus by directly targeting 3′-leader region of genomic RNA

RNA binding motif 4 inhibits the replication of ebolavirus by directly targeting 3′-leader region of genomic RNA

Hippo signaling pathway regulates Ebola virus transcription and egress

The cellular protein phosphatase 2A is a crucial host factor for Marburg virus transcription

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