The E89K Mutation in the Matrix Protein of the Measles Virus Affects In Vitro Cell Death and Virus Replication Efficiency in Human PBMC

Dong, Jing; Zhu, Wei; Saito, Akatsuki; Goto, Yoshitaka; Iwata, Hiroyuki; Haga, Takeshi

doi:10.2174/1874357901206010068

Cited by 2 publications

(3 citation statements)

References 16 publications

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“…The aa substitutions in the M protein, namely E89K (PMV-2990) and R175G (DMV-muc), have also been shown to be important in MV cell culture adaptation 30 , 31 . In particular, experiments with the E89K substitution in MV have demonstrated that this mutation can facilitate virus infection in Vero cells and cotton rats 31 , 47 . Interestingly, some morbillivirus vaccine strains also contain these changes at positions 5 and 12 of the leader sequence, which we identified in this study (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary evidence for multi-host transmission of cetacean morbillivirus

Jo¹,

Kruppa

Habierski³

et al. 2018

Emerging Microbes & Infections

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Cetacean morbillivirus (CeMV) has emerged as the pathogen that poses the greatest risk of triggering epizootics in cetacean populations worldwide, and has a high propensity for interspecies transmission, including sporadic infection of seals. In this study, we investigated the evolutionary history of CeMV by deep sequencing wild-type viruses from tissue samples representing cetacean species with different spatiotemporal origins. Bayesian phylogeographic analysis generated an estimated evolutionary rate of 2.34 × 10−4 nucleotide substitutions/site/year and showed that CeMV evolutionary dynamics are neither host-restricted nor location-restricted. Moreover, the dolphin morbillivirus strain of CeMV has undergone purifying selection without evidence of species-specific mutations. Cell-to-cell fusion and growth kinetics assays demonstrated that CeMV can use both dolphin and seal CD150 as a cellular receptor. Thus, it appears that CeMV can readily spread among multiple cetacean populations and may pose an additional spillover risk to seals.

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Section: Discussionmentioning

confidence: 99%

Evolutionary evidence for multi-host transmission of cetacean morbillivirus

Jo¹,

Kruppa

Habierski³

et al. 2018

Emerging Microbes & Infections

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“…1D). Note that we conducted a more thorough mutational analysis of the glutamic acid residue at position 89 (Table 1), given that this amino acid was reported to influence MeV replication both in vitro and in vivo (36)(37)(38)(39)(40). Overall, we intended in this study to generate M mutants exclusively deficient in triggering late stages of the viral life cycle (i.e., membrane budding) while preserving other functions mostly unaltered (i.e., folding, intracellular transport-competence, interaction with the nucleocapsid protein [N], and localization with the plasma membrane).…”

Section: Resultsmentioning

confidence: 99%

“…Additional studies revealed a role of the amino acid at position 89 of MeV-M as an important determinant for adaptation and growth of the virus in Vero cells (36,37). Indeed, while the substitutions E89G and E89K allowed the virus to adapt to Vero cells, the mutant M-E89K enabled MeV to more efficiently infect cotton rats and affect virus replication in human peripheral blood mononuclear cells (PBMCs) (37)(38)(39)(40). Finally, M-driven membrane budding may also rely on its capacity to associate with cellular membranes, as well as to self-assemble into stable dimers, which in turn may form proper building blocks to assemble high-order oligomers (6,14,19,21,22).…”

mentioning

confidence: 99%

Oligomerization and Cell Egress Controlled by Two Microdomains of Canine Distemper Virus Matrix Protein

Gast

Kadzioch

Milius

et al. 2021

mSphere

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The multimeric matrix (M) protein of clinically relevant paramyxoviruses orchestrates assembly and budding activity of viral particles at the plasma membrane (PM). We identified within the canine distemper virus (CDV) M protein two microdomains, potentially assuming α-helix structures, which are essential for membrane budding activity. Remarkably, while two rationally designed microdomain M mutants (E89R, microdomain 1 and L239D, microdomain 2) preserved proper folding, dimerization, interaction with the nucleocapsid protein, localization at and deformation of the PM, the virus-like particle formation, as well as production of infectious virions (as monitored using a membrane budding-complementation system), were, in sharp contrast, strongly impaired. Of major importance, raster image correlation spectroscopy (RICS) revealed that both microdomains contributed to finely tune M protein mobility specifically at the PM. Collectively, our data highlighted the cornerstone membrane budding-priming activity of two spatially discrete M microdomains, potentially by coordinating the assembly of productive higher oligomers at the PM. IMPORTANCE Despite the availability of efficient vaccines, morbilliviruses (e.g., canine distemper virus [CDV] and measles virus [MeV]) still cause major health impairments. Although antivirals may support vaccination campaigns, approved inhibitors are to date still lacking. Targeting late stages of the viral life cycle (i.e., the cell exit system) represents a viable option to potentially counteract morbilliviral infections. The matrix (M) protein of morbillivirus is a major contributor to membrane budding activity and is assumed to assemble into dimers that further associate to form higher oligomers. Here, we rationally engineered M protein variants with modifications in two microdomains that potentially locate at dimer-dimer interfaces. Our results spotlight the cornerstone impact of both microdomains in membrane budding activity and further suggest a role of finely tuned high-order oligomer formation in regulating late stages of cell exit. Collectively, our findings highlight two microdomains in the morbilliviral M protein as novel attractive targets for drug design.

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The E89K Mutation in the Matrix Protein of the Measles Virus Affects In Vitro Cell Death and Virus Replication Efficiency in Human PBMC

Cited by 2 publications

References 16 publications

Evolutionary evidence for multi-host transmission of cetacean morbillivirus

Evolutionary evidence for multi-host transmission of cetacean morbillivirus

Oligomerization and Cell Egress Controlled by Two Microdomains of Canine Distemper Virus Matrix Protein

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