scholarly journals Host-Driven Phosphorylation Appears to Regulate the Budding Activity of the Lassa Virus Matrix Protein

Pathogens ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 97 ◽  
Author(s):  
Christopher Ziegler ◽  
Philip Eisenhauer ◽  
Inessa Manuelyan ◽  
Marion Weir ◽  
Emily Bruce ◽  
...  
Keyword(s):  
Protein Function ◽  
Matrix Protein ◽  
Rna Virus ◽  
Hemorrhagic Fever ◽  
Polymerase Activity ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Protein Z ◽  
Western Africa ◽  
Z Protein

Lassa mammarenavirus (LASV) is an enveloped RNA virus that can cause Lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western Africa. The arenavirus matrix protein Z has several functions during the virus life cycle, including coordinating viral assembly, driving the release of new virus particles, regulating viral polymerase activity, and antagonizing the host antiviral response. There is limited knowledge regarding how the various functions of Z are regulated. To investigate possible means of regulation, mass spectrometry was used to identify potential sites of phosphorylation in the LASV Z protein. This analysis revealed that two serines (S18, S98) and one tyrosine (Y97) are phosphorylated in the flexible N- and C-terminal regions of the protein. Notably, two of these sites, Y97 and S98, are located in (Y97) or directly adjacent to (S98) the PPXY late domain, an important motif for virus release. Studies with non-phosphorylatable and phosphomimetic Z proteins revealed that these sites are important regulators of the release of LASV particles and that host-driven, reversible phosphorylation may play an important role in the regulation of LASV Z protein function.

scholarly journals Crystal Structure of the Oligomeric Form of Lassa Virus Matrix Protein Z

2016 ◽  
Vol 90 (9) ◽  
pp. 4556-4562 ◽  
Author(s):  
Kathryn M. Hastie ◽  
Michelle Zandonatti ◽  
Tong Liu ◽  
Sheng Li ◽  
Virgil L. Woods ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Life Cycle ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Viral Life Cycle ◽  
Lassa Virus ◽  
Protein Z ◽  
Basic Center ◽  
Oligomeric Form ◽  
Oligomeric Forms

ABSTRACTThe arenavirus matrix protein Z is highly multifunctional and occurs in both monomeric and oligomeric forms. The crystal structure of a dodecamer of Z from Lassa virus, presented here, illustrates a ring-like structure with a highly basic center. Mutagenesis demonstrates that the dimeric interface within the dodecamer and a Lys-Trp-Lys triad at the center of the ring are important for oligomerization. This structure provides an additional template to explore the many functions of Z.IMPORTANCEThe arenavirus Lassa virus causes hundreds of thousands of infections each year, many of which develop into fatal hemorrhagic fever. The arenavirus matrix protein Z is multifunctional, with at least four distinct roles. Z exists in both monomeric and oligomeric forms, each of which likely serves a specific function in the viral life cycle. Here we present the dodecameric form of Lassa virus Z and demonstrate that Z forms a “wreath” with a highly basic center. This structure and that of monomeric Z now provide a pair of critical templates by which the multiple roles of Z in the viral life cycle may be interpreted.

scholarly journals E3 Ligase ITCH Interacts with the Z Matrix Protein of Lassa and Mopeia Viruses and Is Required for the Release of Infectious Particles

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 49 ◽  
Author(s):  
Nicolas Baillet ◽  
Sophie Krieger ◽  
Xavier Carnec ◽  
Mathieu Mateo ◽  
Alexandra Journeaux ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Matrix Protein ◽  
Virus Assembly ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Lassa Virus ◽  
Yeast Two Hybrid ◽  
Ubiquitin Ligase Activity ◽  
Two Hybrid

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related, rodent-born mammarenaviruses. LASV is the causative agent of Lassa fever, a deadly hemorrhagic fever endemic in West Africa, whereas MOPV is non-pathogenic in humans. The Z matrix protein of arenaviruses is essential to virus assembly and budding by recruiting host factors, a mechanism that remains partially defined. To better characterize the interactions involved, a yeast two-hybrid screen was conducted using the Z proteins from LASV and MOPV as a bait. The cellular proteins ITCH and WWP1, two members of the Nedd4 family of HECT E3 ubiquitin ligases, were found to bind the Z proteins of LASV, MOPV and other arenaviruses. The PPxY late-domain motif of the Z proteins is required for the interaction with ITCH, although the E3 ubiquitin-ligase activity of ITCH is not involved in Z ubiquitination. The silencing of ITCH was shown to affect the replication of the old-world mammarenaviruses LASV, MOPV, Lymphocytic choriomeningitis virus (LCMV) and to a lesser extent Lujo virus (LUJV). More precisely, ITCH was involved in the egress of virus-like particles and the release of infectious progeny viruses. Thus, ITCH constitutes a novel interactor of LASV and MOPV Z proteins that is involved in virus assembly and release.

scholarly journals Effect of Strain Variations on Lassa Virus Z Protein-Mediated Human RIG-I Inhibition

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 907
Author(s):  
Qinfeng Huang ◽  
Xiaoying Liu ◽  
Morgan Brisse ◽  
Hinh Ly ◽  
Yuying Liang
Keyword(s):  
Matrix Protein ◽  
Neurological Diseases ◽  
Clinical Manifestations ◽  
Hemorrhagic Fever ◽  
Lassa Virus ◽  
Type I ◽  
Human Pathogens ◽  
Protein Z ◽  
Disease Heterogeneity ◽  
Viral Virulence

Mammarenaviruses include several known human pathogens, such as the prototypic lymphocytic choriomeningitis virus (LCMV) that can cause neurological diseases and Lassa virus (LASV) that causes endemic hemorrhagic fever infection. LASV-infected patients show diverse clinical manifestations ranging from asymptomatic infection to hemorrhage, multi-organ failures and death, the mechanisms of which have not been well characterized. We have previously shown that the matrix protein Z of pathogenic arenaviruses, including LASV and LCMV, can strongly inhibit the ability of the innate immune protein RIG-I to suppress type I interferon (IFN-I) expression, which serves as a mechanism of viral immune evasion and virulence. Here, we show that Z proteins of diverse LASV isolates derived from rodents and humans have a high degree of sequence variations at their N- and C-terminal regions and produce variable degrees of inhibition of human RIG-I (hRIG-I) function in an established IFN-β promoter-driven luciferase (LUC) reporter assay. Additionally, we show that Z proteins of four known LCMV strains can also inhibit hRIG-I at variable degrees of efficiency. Collectively, our results confirm that Z proteins of pathogenic LASV and LCMV can inhibit hRIG-I and suggest that strain variations of the Z proteins can influence their efficiency to suppress host innate immunity that might contribute to viral virulence and disease heterogeneity.

scholarly journals Cells Expressing the RING Finger Z Protein Are Resistant to Arenavirus Infection

2004 ◽  
Vol 78 (6) ◽  
pp. 2979-2983 ◽  
Author(s):  
Tatjana I. Cornu ◽  
Heinz Feldmann ◽  
Juan Carlos de la Torre
Keyword(s):  
Recombinant Adenovirus ◽  
Ring Finger ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Surface Glycoprotein ◽  
Protein Z ◽  
Virus Transcription ◽  
Lassa Fever Virus ◽  
Z Protein

ABSTRACT Arenaviruses include Lassa fever virus (LFV) and the South American hemorrhagic fever viruses. These viruses cause severe human disease, and they pose a threat as agents of bioterrorism. Arenaviruses are enveloped viruses with a bisegmented negative-strand RNA genome whose proteomic capability is limited to four polypeptides: nucleoprotein (NP); surface glycoprotein (GP), which is proteolytically processed into GP1 and GP2; polymerase (L); and a small (11-kDa) RING finger protein (Z). Our investigators have previously shown that Z has a strong inhibitory activity on RNA synthesis mediated by the polymerase of the prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). In this report we show that cells transduced with a replication-deficient recombinant adenovirus expressing Z (rAd-Z) are resistant to LCMV and LFV infection. Virus cell entry mediated by LCMV or LFV GP was not affected in rAd-Z-transduced cells, but both virus transcription and replication were strongly and specifically inhibited, which resulted in a dramatic reduction in production of infectious virus. These findings open new avenues for developing antiviral strategies to combat the highly pathogenic human arenaviruses, including LFV.

scholarly journals Lassa Virus Circulation in Small Mammal Populations in Bo District, Sierra Leone

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 28
Author(s):  
Umaru Bangura ◽  
Jacob Buanie ◽  
Joyce Lamin ◽  
Christopher Davis ◽  
Gédéon Ngiala Bongo ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Sierra Leone ◽  
Small Mammal ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Lassa Virus ◽  
Sierra Leonean ◽  
Bayesian Phylogenetic Analysis ◽  
Prevalent Species ◽  
Lineage Iv

Lassa fever is a viral hemorrhagic fever caused by the Lassa virus LASV, which was first isolated in the rodent Mastomys natalensis in 1974 in Kenema, Sierra Leone. As little is known about the abundance and the presence of LASV in rodents living in the Bo area, we carried out a small mammal longitudinal population survey. A standardized trapping session was performed in various habitats and seasons in six villages over two years (2014–2016) and samples collected were tested for arenavirus IgG and LASV. A Bayesian phylogenetic analysis was performed on sequences identified by PCR. A total of 1490 small mammals were collected, and 16 rodent species were identified, with M. natalensis (355, 24%) found to be the most prevalent species. Forty-one (2.8%) samples were IgG positive, and 31 of these were trapped in homes and 10 in surrounding vegetation. Twenty-nine of 41 seropositive rodents were M. natalensis. We detected four LASV by PCR in two villages, all found in M. natalensis. Phylogenetic analysis showed that the sequences were distributed within the Sierra Leonean clade within lineage IV, distinguishing a Bo sub-clade older than a Kenema sub-clade. Compared to other settings, we found a low abundance of M. natalensis and a low circulation of LASV in rodents in villages around Bo district.

scholarly journals Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 138 ◽  
Author(s):  
Mantlo ◽  
Paessler ◽  
Huang
Keyword(s):  
Clinical Importance ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Innate Immune ◽  
Host Immune System ◽  
Lassa Virus ◽  
Type I ◽  
Highly Pathogenic ◽  
The Family ◽  
Pro Inflammatory Cytokines

The family Arenaviridae contains several pathogens of major clinical importance. The Old World (OW) arenavirus Lassa virus is endemic in West Africa and is estimated to cause up to 300,000 infections each year. The New World (NW) arenaviruses Junín and Machupo periodically cause hemorrhagic fever outbreaks in South America. While these arenaviruses are highly pathogenic in humans, recent evidence indicates that pathogenic OW and NW arenaviruses interact with the host immune system differently, which may have differential impacts on viral pathogenesis. Severe Lassa fever cases are characterized by profound immunosuppression. In contrast, pathogenic NW arenavirus infections are accompanied by elevated levels of Type I interferon and pro-inflammatory cytokines. This review aims to summarize recent findings about interactions of these pathogenic arenaviruses with the innate immune machinery and the subsequent effects on adaptive immunity, which may inform the development of vaccines and therapeutics against arenavirus infections.

scholarly journals Lassa Virus Z Protein Is a Matrix Protein and Sufficient for the Release of Virus-Like Particles

2003 ◽  
Vol 77 (23) ◽  
pp. 12927-12927 ◽  
Author(s):  
Thomas Strecker ◽  
Robert Eichler ◽  
Jan ter Meulen ◽  
Winfried Weissenhorn ◽  
Hans Dieter Klenk ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Lassa Virus ◽  
Virus Like Particles ◽  
Z Protein

scholarly journals A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 133 ◽  
Author(s):  
Maria S. Salvato ◽  
Arban Domi ◽  
Camila Guzmán-Cardozo ◽  
Sandra Medina-Moreno ◽  
Juan Carlos Zapata ◽  
...  
Keyword(s):  
Single Dose ◽  
Matrix Protein ◽  
Lethal Dose ◽  
Health Impact ◽  
Lassa Virus ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Lethal Challenge ◽  
Virus Like Particles ◽  
Virus Challenge

Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus.

scholarly journals Analysis of Assembly and Budding of Lujo Virus

2015 ◽  
Vol 90 (6) ◽  
pp. 3257-3261 ◽  
Author(s):  
Shuzo Urata ◽  
Jacqueline Weyer ◽  
Nadia Storm ◽  
Yukiko Miyazaki ◽  
Petrus Jansen van Vuren ◽  
...  
Keyword(s):  
Cell Surface ◽  
Matrix Protein ◽  
Hemorrhagic Fever ◽  
Surface Glycoprotein ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Cell Surface Glycoprotein ◽  
Particle Release ◽  
Viral Release ◽  
Virus Like Particle

The recently identified arenavirus Lujo virus (LUJV) causes fatal hemorrhagic fever in humans. We analyzed its mechanism of viral release driven by matrix protein Z and the cell surface glycoprotein precursor GPC. The L domains in Z are required for efficient virus-like particle release, but Tsg101, ALIX/AIP1, and Vps4A/B are unnecessary for budding. LUJV GPC is cleaved by site 1 protease (S1P) at the RKLM motif, and treatment with the S1P inhibitor PF-429242 reduced LUJV production.

scholarly journals Efficient Budding of the Tacaribe Virus Matrix Protein Z Requires the Nucleoprotein

2010 ◽  
Vol 84 (7) ◽  
pp. 3603-3611 ◽  
Author(s):  
Allison Groseth ◽  
Svenja Wolff ◽  
Thomas Strecker ◽  
Thomas Hoenen ◽  
Stephan Becker
Keyword(s):  
Essential Role ◽  
New World ◽  
Matrix Protein ◽  
Protein Z ◽  
Virus Like Particles ◽  
Endosomal Sorting ◽  
Virus Particles ◽  
Tacaribe Virus ◽  
C Terminus ◽  
Z Protein

ABSTRACT The Z protein has been shown for several arenaviruses to serve as the viral matrix protein. As such, Z provides the principal force for the budding of virus particles and is capable of forming virus-like particles (VLPs) when expressed alone. For most arenaviruses, this activity has been shown to be linked to the presence of proline-rich late-domain motifs in the C terminus; however, for the New World arenavirus Tacaribe virus (TCRV), no such motif exists within Z. It was recently demonstrated that while TCRV Z is still capable of functioning as a matrix protein to induce the formation of VLPs, neither its ASAP motif, which replaces a canonical PT/SAP motif in related viruses, nor its YxxL motif is involved in budding, leading to the suggestion that TCRV uses a novel budding mechanism. Here we show that in comparison to its closest relative, Junin virus (JUNV), TCRV Z buds only weakly when expressed in isolation. While this budding activity is independent of the ASAP or YxxL motif, it is significantly enhanced by coexpression with the nucleoprotein (NP), an effect not seen with JUNV Z. Interestingly, both the ASAP and YxxL motifs of Z appear to be critical for the recruitment of NP into VLPs, as well as for the enhancement of TCRV Z-mediated budding. While it is known that TCRV budding remains dependent on the endosomal sorting complex required for transport, our findings provide further evidence that TCRV uses a budding mechanism distinct from that of other known arenaviruses and suggest an essential role for NP in this process.

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