Evidence That HIV Budding in Primary Macrophages Occurs through the Exosome Release Pathway

Nguyen, Deborah G.; Booth, Amy M.; Gould, Stephen J.; Hildreth, James E. K.

doi:10.1074/jbc.m309009200

Cited by 293 publications

(273 citation statements)

References 51 publications

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“…Relevance to Retrovirus Budding-Previous studies have noted a number of similarities between EMV biogenesis and retrovirus budding, including the molecular composition of the released particles, sites of budding in different cell types, and the targeting signals that deliver proteins to EMVs and retrovirus particles (7,23,24,51). These and other observations support the hypothesis that retrovirus budding is, at its core, a form of EMV biogenesis (4).…”

Section: Discussionmentioning

confidence: 60%

Protein Targeting to Exosomes/Microvesicles by Plasma Membrane Anchors

Shen

Yang

et al. 2011

Journal of Biological Chemistry

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247

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Animal cells secrete small vesicles, otherwise known as exosomes and microvesicles (EMVs). A short, N-terminal acylation tag can target a highly oligomeric cytoplasmic protein, TyA, into secreted vesicles (Fang, Y., Wu, N., Gan, X., Yan, W., Morell, J. C., and Gould, S. J. (2007) PLoS Biol. 5, 1267-1283). However, it is not clear whether this is true for other membrane anchors or other highly oligomeric, cytoplasmic proteins. We show here that a variety of plasma membrane anchors can target TyA-GFP to sites of vesicle budding and into EMVs, including: (i) a myristoylation tag; (ii) a phosphatidylinositol-(4,5)-bisphosphate (PIP 2 )-binding domain; (iii), a phosphatidylinositol-(3,4,5)-trisphosphate-binding domain; (iv) a prenylation/palmitoylation tag, and (v) a type-1 plasma membrane protein, CD43. However, the relative budding efficiency induced by these plasma membrane anchors varied over a 10-fold range, from 100% of control (AcylTyA-GFP) for the myristoylation tag and PIP 2 -binding domain, to one-third or less for the others, respectively. Targeting TyA-GFP to endosome membranes by fusion to a phosphatidylinositol 3-phosphate-binding domain induced only a slight budding of TyA-GFP, ϳ2% of control, and no budding was observed when TyA-GFP was targeted to Golgi membranes via a phosphatidylinositol 4-phosphate-binding domain. We also found that a plasma membrane anchor can target two other highly oligomeric, cytoplasmic proteins to EMVs. These observations support the hypothesis that plasma membrane anchors can target highly oligomeric, cytoplasmic proteins to EMVs. Our data also provide additional parallels between EMV biogenesis and retrovirus budding, as the anchors that induced the greatest budding of TyA-GFP are the same as those that mediate retrovirus budding.Animal cells release single membrane vesicles that have the same topology as the cell and a variable diameter of ϳ50 -250 nm (1-8). These vesicles mediate the secretion of a wide variety of proteins, lipids, mRNAs, and micro RNAs, interact with neighboring cells, and can thereby transmit signals, proteins, lipids, and nucleic acids from cell to cell (3, 9 -11). Furthermore, the ability of vesicle-derived nucleic acids to alter gene expression in neighboring cells makes it likely that secreted vesicles can fuse with neighboring cells in a nonviral pathway of intercellular vesicle traffic. Not surprisingly, there is increasing evidence that secreted vesicles play important roles in normal physiological processes (e.g. immune signaling (2), development (12, 13) and in human disease (e.g. cancer (14 -16), amyloidopathies (17-19), and viral infections (4, 7, 20 -22)).Current models posit that there might be two separate pathways for the formation of small secreted vesicles: microvesicle biogenesis, which involves vesicle budding directly from the plasma membrane (PM) 2 ; and exosome biogenesis, which involves vesicle budding into endosomes to form multivesicular bodies (MVBs), followed by MVB-PM fusion (3,8). However, differentiating between microvesic...

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Section: Discussionmentioning

confidence: 60%

Protein Targeting to Exosomes/Microvesicles by Plasma Membrane Anchors

Shen

Yang

et al. 2011

Journal of Biological Chemistry

Self Cite

247

228

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“…The WD40 domain controls this behavior, likely by mediating the formation of higher-order oligomers. It has been reported that high-order oligomerization and membrane-binding motifs artificially target cytosolic proteins to membrane patches, which accumulate at the lagging edge in polarized cells (48)(49)(50)(51)(52). Oligomerizing membrane microdomain components also enrich at the rear of polarized neutrophils or T cells (53)(54)(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Novel protein Callipygian defines the back of migrating cells

Swaney

Borleis

Iglesias

et al. 2015

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

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Asymmetric protein localization is essential for cell polarity and migration. We report a novel protein, Callipygian (CynA), which localizes to the lagging edge before other proteins and becomes more tightly restricted as cells polarize; additionally, it accumulates in the cleavage furrow during cytokinesis. CynA protein that is tightly localized, or "clustered," to the cell rear is immobile, but when polarity is disrupted, it disperses throughout the membrane and responds to uniform chemoattractant stimulation by transiently localizing to the cytosol. These behaviors require a pleckstrin homology-domain membrane tether and a WD40 clustering domain, which can also direct other membrane proteins to the back. Fragments of CynA lacking the pleckstrin homology domain, which are normally found in the cytosol, localize to the lagging edge membrane when coexpressed with full-length protein, showing that CynA clustering is mediated by oligomerization. Cells lacking CynA have aberrant lateral protrusions, altered leading-edge morphology, and decreased directional persistence, whereas those overexpressing the protein display exaggerated features of polarity. Consistently, actin polymerization is inhibited at sites of CynA accumulation, thereby restricting protrusions to the opposite edge. We suggest that the mutual antagonism between CynA and regions of responsiveness creates a positive feedback loop that restricts CynA to the rear and contributes to the establishment of the cell axis.chemotaxis | polarity | asymmetry | Dictyostelium | protein localization

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“…One such virus, HIV-1, had been proposed to bud into late endosomes in some cells (42)(43)(44), but recent results imply that HIV-1 assembly and budding occur at the plasma membrane, with endosomal localization of virions occurring by internalization from the plasma membrane (45). Thus, it remains a significant question whether MVB functions are required for virion budding into internal compartments, as occurs for HBV, the SARS coronavirus, and some other viruses.…”

Section: H Epatitis B Virus (Hbv) Chronically Infects 350 Millionmentioning

confidence: 98%

Involvement of host cellular multivesicular body functions in hepatitis B virus budding

Watanabe

Sorensen

Naito

et al. 2007

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

231

239

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Hepatitis B virus (HBV) is a major human pathogen that chronically infects Ϸ350 million people, causing liver disease and liver cancer. HBV virions bud into an endoplasmic reticulum (ER)-associated intracellular compartment, but the mechanisms of HBV assembly, budding, and release remain poorly understood. Budding of retroviruses and some other enveloped RNA viruses from plasma membranes requires host functions involved in protein sorting into late endosomal multivesicular bodies (MVBs). To determine whether budding of DNA-containing HBV virions at intracellular membranes also involves MVB functions, we used immunofluorescence to show that, in human hepatoma cells, HBV envelope protein colocalizes with MVB proteins AIP1/ALIX and VPS4B. We also found that a dominant negative (DN) AIP1 mutant inhibited production and/or release of enveloped virions without significant effects on intracellular nucleocapsid formation, whereas DN VPS4B inhibited both nucleocapsid production and budding. By contrast, DN AIP1 and VPS4 had no effect on the efficiency of release of enveloped, nucleocapsid-lacking HBV subviral particles, which are produced in vast excess over virions, and dramatically increased the release of unenveloped, naked nucleocapsids by an apparently nonlytic route. Thus, host MVB functions are required for efficient budding and release of enveloped HBV virions and may be a valuable target for HBV control. Moreover, HBV enveloped virions, enveloped subviral particles, and unenveloped nucleocapsids are all released by distinct pathways with separate host factor requirements.antiviral control ͉ hepadnavirus ͉ vacuolar protein sorting ͉ virus replication ͉ virus-host interaction

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Evidence That HIV Budding in Primary Macrophages Occurs through the Exosome Release Pathway

Cited by 293 publications

References 51 publications

Protein Targeting to Exosomes/Microvesicles by Plasma Membrane Anchors

Protein Targeting to Exosomes/Microvesicles by Plasma Membrane Anchors

Novel protein Callipygian defines the back of migrating cells

Involvement of host cellular multivesicular body functions in hepatitis B virus budding

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