The emerging shape of the ESCRT machinery

Williams, Roger L.; Urbé, Sylvie

doi:10.1038/nrm2162

Cited by 653 publications

(690 citation statements)

References 135 publications

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“…For example, Gag alone can form extracellular virus-like particles in the absence of other viral proteins [11] and Gag molecules can spontaneously assemble into spherical, immature viruslike particles in vitro [12][13][14]. Nevertheless, although Gag itself encodes the necessary tertiary and quaternary interactions, it must be emphasized that assembly requires nonspecific RNA interactions both in vivo and in vitro, and is assisted by host factors in vivo, including trafficking factors, assembly chaperones, and the ESCRT budding pathway, as reviewed elsewhere [15][16][17][18].…”

Section: Gag As An Assembly Machinementioning

confidence: 99%

The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

409

422

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HIV assembly and replication proceed through formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is initiated by proteolytic processing of Gag, which induces conformational changes in the CA domain and results in assembly of the distinctive conical capsid. Retroviral capsids are organized following the principles of fullerene cones, and the hexagonal CA lattice is stabilized by three distinct interfaces. Recently identified inhibitors of viral maturation act by disrupting the final stage of Gag processing, or by inhibiting formation of a critical intermolecular CA-CA interface in the mature capsid. Following release into a new host cell, the capsid disassembles and host cell factors can potently restrict this stage of retroviral replication. Here, we review the structures of immature and mature HIV virions, focusing on recent studies that have defined the global organization of the immature Gag lattice, identified sites likely to undergo conformational changes during maturation, revealed the molecular structure of the mature capsid lattice, demonstrated that capsid architectures are conserved, identified the first capsid assembly inhibitors, and begun to uncover the remarkable biology of the mature capsid.

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Section: Gag As An Assembly Machinementioning

confidence: 99%

The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

409

422

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“…2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.…”

mentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

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Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal exosomes' following activation-induced fusion of the MVB with the plasma membrane. Diacylglycerol (DAG) and diacylglycerol kinase α (DGKα) regulate MVB maturation and polarized traffic, as well as subsequent secretion of pro-apoptotic exosomes, but the molecular basis underlying these phenomena remains unclear. Here we identify protein kinase D (PKD) family members as DAG effectors involved in MVB genesis and secretion. We show that the inducible secretion of exosomes is enhanced when a constitutively active PKD1 mutant is expressed in T lymphocytes, whereas exosome secretion is impaired in PKD2-deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of PKD2-deficient T lymphoblasts showed the presence of large, immature MVB-like vesicles and demonstrated defects in cytotoxic activity and in activation-induced cell death. Using pharmacological and genetic tools, we show that DGKα regulates PKD1/2 subcellular localization and activation. Our studies demonstrate that PKD1/2 is a key regulator of MVB maturation and exosome secretion, and constitutes a mediator of the DGKα effect on MVB secretory traffic. Exosomes are nanovesicles that form as intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs) and are then secreted by numerous cell types. 1 ILVs are generated by inward budding of late endosome limiting membrane in a precisely regulated maturation process. 2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.Exosomes participate in many biological processes related to T-cell receptor (TCR)-triggered immune responses, including T lymphocyte-mediated cytotoxicity and activationinduced cell death (AICD), antigen presentation and intercellular miRNA exchange. [10][11][12][13][14][15] The discovery of exosome involvement in these responses increased interest in the regulation of exosome biogenesis and secretory traffic, with special attention to the contribution of lipids such as ceramide and DAG, as well as DAG-binding proteins. 14,16-21 These studies suggest that positive and negative DAG regulators may control secretory traffic. By transforming DAG into phosphatidic acid (PA), diacylglycerol kinase α (DGKα) is essential for the negative control of DAG function in T lymphocytes. 22 DGKα translocates transiently to the T-cell membrane after human muscarinic type 1 receptor (HM1R) triggering or to the immune synapse (IS) after TCR stimulation; at these subcellular locations, DGKα acts as a negative modulator of phospholipase C (PLC)-generated DAG. 23,24 The secretory vesicle pathway involves several DAGc...

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“…ESCRT-II, together with ESCRT-0, is the only component of the ESCRT machinery that can directly interact with membrane phosphoinosites (Wollert et al, 2009). Particularly, the Vps27 subunit of ESCRT-0 contains a FYVE-domain able to interact with PtdIns3P but a direct role of ESCRT-0 in abscission has so far never been shown (Williams and Urbe, 2007). Conversely, the ESCRT-II subunit, VPS36, has a GLUE-domain with a structural similarity to the pleckstrin homology (PH) domain, that can associate to PtdIns (Slagsvold et al, 2005;Teo et al, 2006;Teo et al, 2004).…”

Section: Escrt and Ptdins3p: Potential Connections And Future Directimentioning

confidence: 99%

Cytokinetic Abscission: Phosphoinositides and ESCRTs Direct the Final Cut

Gulluni

Martini

Hirsch

2017

J of Cellular Biochemistry

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Cytokinetic abscission involves the fine and regulated recruitment of membrane remodeling proteins that participate in the abscission of the intracellular bridge that connects the two dividing cells. This essential process is mediated by the concomitant activity of the endosomal sorting complex required for transport (ESCRT) and the vesicular trafficking directed to the midbody.Phosphoinositides (PtdIns), produced at plasma membrane and endosomes, act as molecular intermediates by recruiting effector proteins involved in multiple cellular processes, such as intracellular signalling, endo-and exo-cytosis and membrane remodelling events. Emerging evidences suggest that PtdIns have an active role in recruiting key elements that control the stability and the remodelling of the cytoskeleton from the furrow ingression to the abscission, at the end of cytokinesis. Accordingly, a possible concomitant and coordinated activity between PtdIns production and ESCRT machinery assembly could also exist and recent findings are pointing the attention on poorly understood ESCRT subunits potentially able to associate with PtdIns rich membranes. Although further studies are required to link PtdIns to ESCRT machinery during abscission, this might represent a promising field of study.

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The emerging shape of the ESCRT machinery

Cited by 653 publications

References 135 publications

The structural biology of HIV assembly

The structural biology of HIV assembly

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Cytokinetic Abscission: Phosphoinositides and ESCRTs Direct the Final Cut

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