ALIX/AIP1 Is Required for NP Incorporation into Mopeia Virus Z-Induced Virus-Like Particles

Shtanko, Olena; Watanabe, Shinji; Jasenosky, Luke D.; Watanabe, Tokiko; Kawaoka, Yoshihiro

doi:10.1128/jvi.01984-10

Cited by 43 publications

(51 citation statements)

References 49 publications

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“…Recent studies showed that mutation of Y57 in TCRV Z almost completely blocked the incorporation of N protein into Z-directed VLPs, though it had no effect on Z budding activity (18,50). Similar results were observed for Mopeia virus Z protein, whose YLCL sequence was also shown to be needed for its interaction with a cellular protein (AIP1) of the multivesicular body pathway (45). In light of our findings demonstrating that TCRV Z residues Y57 and L58 are important for L binding (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…Moreover, the Z protein plays an essential role in virion assembly and budding, sharing several characteristics with other negative-strand RNA virus matrix proteins. Expression of Z protein in mammalian cells, in the absence of other viral proteins, leads to the assembly and budding of virus-like particles (VLPs) (8,36,45,46,50). Furthermore, the Z protein C-terminal region contains prolinerich late domains (PTAP and/or PPPY), which are important for the recruitment of host proteins that assist in the late stages of budding (36,49).…”

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confidence: 99%

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Molecular Determinants of Arenavirus Z Protein Homo-Oligomerization and L Polymerase Binding

Loureiro

Wilda

Macleod

et al. 2011

J Virol

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The arenavirus Z is a zinc-binding RING protein that has been implicated in multiple functions during the viral life cycle. These roles of Z involve interactions with viral and cellular proteins that remain incompletely understood. In this regard, Z inhibits viral RNA transcription and replication through direct interaction with the viral L polymerase. Here, we defined the L-binding domain of Tacaribe virus (TCRV) Z protein and the structural requirements mediating Z homo-oligomerization. By using site-directed mutagenesis, coimmunoprecipitation, and functional assays, we showed that residues R37, N39, W44, L50, and Y57, located around the zinc coordination site I, play a critical role in the Z-L interaction. We also found that Z protein from either TCRV or the pathogenic Junin virus (JUNV) self-associates into oligomeric forms in mammalian cells. Importantly, mutation of the myristoylation site, the strictly conserved residue G at position 2, severely impaired the ability of both TCRV Z and JUNV Z to self-interact as well as their capacity to accumulate at the plasma membrane, strongly suggesting that Z homo-oligomerization is associated with its myristoylation and cell membrane targeting. In contrast, disruption of the RING structure or substitution of W44 or N39, which are critical for L protein recognition, did not affect Z self-binding. Overall, the data presented here indicate that homo-oligomerization is not a requirement for Z-L interaction or Z-mediated polymerase activity inhibition.

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

Molecular Determinants of Arenavirus Z Protein Homo-Oligomerization and L Polymerase Binding

Loureiro

Wilda

Macleod

et al. 2011

J Virol

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“…Thus, RNA-free NP seems to exist exclusively as a trimer, which presumably has biological relevance. Besides being the building block of ribonucleoproteins, NP has additional functions during the life cycle of the virus, such as interaction with L and Z proteins and cellular proteins, budding of particles, suppression of the interferon response, exoribonuclease activity, and nucleotide binding (15)(16)(17)(18)(19)(20)(21)(22)(23). Some of these or other so far unknown functions of NP might be associated specifically with the trimeric configuration.…”

Section: Discussionmentioning

confidence: 99%

“…It physically associates with itself as well as with L and Z proteins (15)(16)(17)(18). The association with Z protein and ALIX/AIP1, an ESCRT-associated host protein, is important for incorporation of NP into virus-like particles (15,(17)(18)(19). In addition, NP acts as an interferon antagonist (20,21).…”

mentioning

confidence: 99%

Structure of the Lassa Virus Nucleoprotein Revealed by X-ray Crystallography, Small-angle X-ray Scattering, and Electron Microscopy

Brunotte

Kerber

Shang

et al. 2011

Journal of Biological Chemistry

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“…Z has been implicated in many facets of the arenavirus replication cycle and is the primary driving force of virion maturation (13). In addition to recruiting the cellular endosomal sorting complex required for transport (ESCRT) machinery to mediate virion budding (13,14), Z has been demonstrated to interact with the translation initiation factor eIF4E (15) as well as retinoic acid inducible gene I (RIG-I), promyelocytic leukemia protein (PML), and proline-rich homeodomain protein (PRH) (16)(17)(18). Thus, Z is positioned at the center of a network of host and viral connections and may serve as a crucial viral sensor of the host cellular environment.…”

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confidence: 99%

Arenavirus Z protein controls viral RNA synthesis by locking a polymerase–promoter complex

Kranzusch

Whelan

2011

Proc. Natl. Acad. Sci. U.S.A.

104

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Arenaviruses form a noncytolytic infection in their rodent hosts, yet can elicit severe hemorrhagic disease in humans. How arenaviruses regulate gene expression remains unclear, and further understanding may provide insight into the dichotomy of these disparate infection processes. Here we reconstitute arenavirus RNA synthesis initiation and gene expression regulation in vitro using purified components and demonstrate a direct role of the viral Z protein in controlling RNA synthesis. Our data reveal that Z forms a species-specific complex with the viral polymerase (L) and inhibits RNA synthesis initiation by impairing L catalytic activity. This Z-L complex locks the viral polymerase in a promoter-bound, catalytically inactive state and may additionally ensure polymerase packaging during virion maturation. Z modulates host factors involved in cellular translation, proliferation, and antiviral signaling. Our data defines an additional role in governing viral RNA synthesis, revealing Z as the center of a network of host and viral connections that regulates viral gene expression.transcription factor | Machupo virus | matrix protein | negative-strand RNA virus | gene regulation T ranscription initiation is a fundamental focal point of gene expression regulation in all orders of life. Modulation of RNA synthesis affords an important response to stress, alterations in growth conditions, and environmental cues. Although initiation of RNA synthesis is often indirectly controlled through gene promoters and accessory signaling elements, regulation also occurs through factors directly interacting with and altering the catalytic potential of the RNA synthesis machinery itself (1). Studies with phage T7 and the T7 lysozyme repressor system have provided an important paradigm for control of viral RNA transcription (2, 3), but these processes remain a mystery for many eukaryotic viruses and medically relevant pathogens. Gene expression regulation is particularly critical for negative-sense RNA viruses of the family Arenaviridae, which must respond to input from the host environment to maintain a noncytolytic infection in their rodent reservoir (4). In stark contrast to this persistent infection, arenavirus infection in humans can lead to severe hemorrhagic fever disease and many arenaviruses represent important emerging pathogens (5). Intriguingly, recent evidence indicates that the balance between persistent and acute viral infection can be altered by a single mutation within the viral polymerase (6). Mechanistic insight into how arenaviruses tune gene expression and control viral RNA synthesis is required to further our understanding of the response of arenavirus infection to various host and cellular environments.Arenaviruses are the simplest of all hemorrhagic fever viruses, with only four viral proteins. The viral genome consists of two segments of single-stranded negative-sense RNA, where each segment encodes two proteins in an ambisense orientation. The small segment encodes for the viral glycoprotein, essential for entr...

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ALIX/AIP1 Is Required for NP Incorporation into Mopeia Virus Z-Induced Virus-Like Particles

Cited by 43 publications

References 49 publications

Molecular Determinants of Arenavirus Z Protein Homo-Oligomerization and L Polymerase Binding

Molecular Determinants of Arenavirus Z Protein Homo-Oligomerization and L Polymerase Binding

Structure of the Lassa Virus Nucleoprotein Revealed by X-ray Crystallography, Small-angle X-ray Scattering, and Electron Microscopy

Arenavirus Z protein controls viral RNA synthesis by locking a polymerase–promoter complex

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