Influenza Virus M2 Protein Mediates ESCRT-Independent Membrane Scission

Rossman, Jeremy S.; Jing, Xiang-Hong; Leser, George P.; Lamb, Robert A.

doi:10.1016/j.cell.2010.08.029

Cited by 453 publications

(767 citation statements)

References 56 publications

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“…RAB11A colocalized with vRNP in transit to the plasma membrane, and disruption of RAB11A protein expression or function impaired vRNP transport from the MTOC. When considered with previous reports of a role for Rab11 in delivering M2 to the plasma membrane and in virion membrane scission and release (7,40), our results suggest an integral, multifactorial role for Rab11 in the influenza virus life cycle.…”

Section: Discussionmentioning

confidence: 86%

“…M2 may have a role in vRNP recruitment as virions produced by viruses encoding M2 that lacks its cytoplasmic tail are defective in nucleoprotein (NP) and genomic RNA incorporation (29). M2 was recently shown to require the cellular Rab11 GTPase for transport to the plasma membrane (40); however, the mechanistic basis for vRNP delivery to virion budding sites has not been clearly elucidated.…”

mentioning

confidence: 99%

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RAB11A Is Essential for Transport of the Influenza Virus Genome to the Plasma Membrane

Eisfeld

Kawakami

Watanabe³

et al. 2011

J Virol

164

213

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Influenza A virus assembly is a complex process that requires the intersection of pathways involved in transporting viral glycoproteins, the matrix protein, and viral genomes, incorporated in the viral ribonucleoprotein (vRNP) complex, to plasma membrane sites of virion formation. Among these virion components, the mechanism of vRNP delivery is the most incompletely understood. Here, we reveal a functional relationship between the cellular Rab11 GTPase isoform, RAB11A, and vRNPs and show that RAB11A is indispensable for proper vRNP transport to the plasma membrane. Using an immunofluorescence-based assay with a monoclonal antibody that recognizes nucleoprotein in the form of vRNP, we demonstrate association between RAB11A and vRNPs at all stages of vRNP cytoplasmic transport. Abrogation of RAB11A expression through small interfering RNA (siRNA) treatment or disruption of RAB11A function by overexpression of dominant negative or constitutively active proteins caused aberrant vRNP intracellular accumulation, retention in the perinuclear region, and lack of accumulation at the plasma membrane. Complex formation between RAB11A and vRNPs was further established biochemically. Our results uncover a critical host factor with an essential contribution to influenza virus genome delivery and reveal a potential role for RAB11A in the transport of ribonucleoprotein cargo.

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

RAB11A Is Essential for Transport of the Influenza Virus Genome to the Plasma Membrane

Eisfeld

Kawakami

Watanabe³

et al. 2011

J Virol

164

213

View full text Add to dashboard Cite

show abstract

“…First, they suggest that the relative abundance of saturated and unsaturated lipids is crucial to tune the interfacial properties of a lipid bilayer and give a potential molecular explanation for why this ratio is tightly controlled 18,32 . A corollary of these results is that liquid-ordered domains, which are enriched in saturated lipids, should be unfavourable for protein hydrophobic insertions, an effect that has been observed experimentally 50,51 . Second, the cumulative effect of membrane shape and composition suggests that the topography of organelle membranes is highly diverse.…”

Section: Discussionmentioning

confidence: 93%

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

et al. 2014

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Two parameters of biological membranes, curvature and lipid composition, direct the recruitment of many peripheral proteins to cellular organelles. Although these traits are often studied independently, it is their combination that generates the unique interfacial properties of cellular membranes. Here, we use a combination of in vivo, in vitro and in silico approaches to provide a comprehensive map of how these parameters modulate membrane adhesive properties. The correlation between the membrane partitioning of model amphipathic helices and the distribution of lipid-packing defects in membranes of different shape and composition explains how macroscopic membrane properties modulate protein recruitment by changing the molecular topography of the membrane interfacial region. Furthermore, our results suggest that the range of conditions that can be obtained in a cellular context is remarkably large because lipid composition and curvature have, under most circumstances, cumulative effects.

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“…The regions C-terminal to the TM helices play different important functional roles. An amphiphilic helix formed by residues 46-60 induces membrane curvature and is involved in viral budding and scission (21)(22)(23), and an intrinsically disordered C-terminal tail (residues 62-97) interacts with the matrix 1 protein during the packing and budding of new virus particles (24,25).…”

Section: Significancementioning

confidence: 99%

XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction

Thomaston

Woldeyes

Nakane

et al. 2017

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

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The M2 proton channel of influenza A is a drug target that is essential for the reproduction of the flu virus. It is also a model system for the study of selective, unidirectional proton transport across a membrane. Ordered water molecules arranged in "wires" inside the channel pore have been proposed to play a role in both the conduction of protons to the four gating His37 residues and the stabilization of multiple positive charges within the channel. To visualize the solvent in the pore of the channel at room temperature while minimizing the effects of radiation damage, data were collected to a resolution of 1.4 Å using an X-ray free-electron laser (XFEL) at three different pH conditions: pH 5.5, pH 6.5, and pH 8.0. Data were collected on the Inward open state, which is an intermediate that accumulates at high protonation of the His37 tetrad. At pH 5.5, a continuous hydrogen-bonded network of water molecules spans the vertical length of the channel, consistent with a Grotthuss mechanism model for proton transport to the His37 tetrad. This ordered solvent at pH 5.5 could act to stabilize the positive charges that build up on the gating His37 tetrad during the proton conduction cycle. The number of ordered pore waters decreases at pH 6.5 and 8.0, where the Inward open state is less stable. These studies provide a graphical view of the response of water to a change in charge within a restricted channel environment.W ater molecules in transmembrane protein pores participate in the transport of protons across the membrane bilayer. This process has been extensively studied experimentally and through computational simulations, particularly in small channels such as gramicidin A and influenza A M2. The movement of ions through channels is coupled to the diffusion of water through the pore, but protons are transported at a rate that is faster than the diffusion of H 3 O + (1, 2). Instead of diffusing through channels, protons move concertedly across networks of hydrogen-bonded waters through what is known as the Grotthuss mechanism (3-5). This mechanism of proton transport was initially discovered by the behavior of water in solution, and it has also been proposed to occur within membrane proteins containing water-filled pores (6-9). The matrix 2 (M2) protein of influenza A is one of the smallest proton-selective channels found in nature. This makes it an ideal system for studying the involvement of water in the selective transport of protons across the membrane. The M2 protein of influenza A is a tetramer made up of four 97-residue-long monomers. M2 is multifunctional, with different functions lying in different regions of the sequence. Residues 1-22 make up a conserved N-terminal domain that assists the incorporation of M2 into the virion (10) and is absent in influenza B viruses. The transmembrane domain of M2 (residues 22-46) is necessary for tetramerization (11) and forms a proton-selective channel (12-15) that is the target of the adamantane class of drugs, amantadine and rimantadine (11,(16)(17)(18). The transme...

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Influenza Virus M2 Protein Mediates ESCRT-Independent Membrane Scission

Cited by 453 publications

References 56 publications

RAB11A Is Essential for Transport of the Influenza Virus Genome to the Plasma Membrane

RAB11A Is Essential for Transport of the Influenza Virus Genome to the Plasma Membrane

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction

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