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After Hrs with HIV.

Amara A, Littman DR - J. Cell Biol. (2003)

Bottom Line: To efficiently bud off from infected cells, HIV and other enveloped viruses hijack the host cellular machinery that is normally involved in vacuolar protein sorting and multivesicular body (MVB) biogenesis.The HIV Gag protein mimics hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a modular adaptor protein that links membrane cargo recognition to its degradation after delivery to MVBs.In contrast to T cells, where HIV budding occurs at the plasma membrane, virus buds into vacuoles of macrophages, a process that may facilitate its spread within the infected host.

View Article: PubMed Central - PubMed

Affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
To efficiently bud off from infected cells, HIV and other enveloped viruses hijack the host cellular machinery that is normally involved in vacuolar protein sorting and multivesicular body (MVB) biogenesis. The HIV Gag protein mimics hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a modular adaptor protein that links membrane cargo recognition to its degradation after delivery to MVBs. In contrast to T cells, where HIV budding occurs at the plasma membrane, virus buds into vacuoles of macrophages, a process that may facilitate its spread within the infected host.

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Mimicry of Hrs function by HIV Gag. The normal function of Hrs, shown in the left panel, is to recruit Tsg101 and the ESCRT-I complex for sorting ubiquitinated (Ub) cargo into the MVB. During HIV infection, HIV Gag mimics Hrs and redirects the ESCRT machinery to the site of viral budding. In T cells (left panel), viral assembly and release occur at the plasma membrane, whereas in macrophages (center) HIV particles accumulate in late endosomes and MVBs. In DCs (right panel), HIV undergoes receptor-mediated endocytosis after binding to DC-SIGN and is recycled to the cell surface. Although the vesicular compartments involved have not been identified, macrophages and DCs may share a mechanism for releasing HIV particles upon contact with T lymphocytes.
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fig2: Mimicry of Hrs function by HIV Gag. The normal function of Hrs, shown in the left panel, is to recruit Tsg101 and the ESCRT-I complex for sorting ubiquitinated (Ub) cargo into the MVB. During HIV infection, HIV Gag mimics Hrs and redirects the ESCRT machinery to the site of viral budding. In T cells (left panel), viral assembly and release occur at the plasma membrane, whereas in macrophages (center) HIV particles accumulate in late endosomes and MVBs. In DCs (right panel), HIV undergoes receptor-mediated endocytosis after binding to DC-SIGN and is recycled to the cell surface. Although the vesicular compartments involved have not been identified, macrophages and DCs may share a mechanism for releasing HIV particles upon contact with T lymphocytes.

Mentions: The new studies have approached the problem of how ESCRT-I is recruited to the site of MVB formation from different angles. Emr and colleagues have used fluorescently tagged proteins to examine their relationship in yeast (Katzmann et al., 2003). They show that GFP-tagged Vps27p colocalizes with DS-Red–tagged FYVE domain of EEA1, an early endosomal marker, and that this requires the FYVE domain of Vps27p (Fig. 1). Moreover, the protein was diffusely distributed in the cytoplasm in PI 3-kinase–deficient vps34 mutant cells, consistent with a requirement for PI(3)P in the recruitment of Vps27p to endosomes (Katzmann et al., 2003). Vps23p was coprecipitated with Vps27p from membrane fractions, but not soluble fractions, of cells transfected with epitope-tagged versions of both proteins, suggesting a direct interaction between Vps27p and ESCRT-I only on endosomal membranes. This interaction did not require either the UIM or the conserved VHS domain of unknown function in the NH2-terminal part of Vps27p. GFP-Vps27p was localized to endosomal structures in a Vps23p-deficient strain, but Vps23p-GFP was diffusely distributed in the cytoplasm in the absence of either Vps27p or Vps34p (Katzmann et al., 2003). These results suggest that Vps27 acts upstream of Vps23, recruiting it to the endosomal limiting membrane once it is activated due to interaction with cargo protein (Fig. 2). Targeting of Vps23p-GFP to endosomal membranes required expression of Vps27p with an intact P/Q-rich COOH-terminal domain, including PSDP and PTVP sequences resembling those in retroviral L domains.


After Hrs with HIV.

Amara A, Littman DR - J. Cell Biol. (2003)

Mimicry of Hrs function by HIV Gag. The normal function of Hrs, shown in the left panel, is to recruit Tsg101 and the ESCRT-I complex for sorting ubiquitinated (Ub) cargo into the MVB. During HIV infection, HIV Gag mimics Hrs and redirects the ESCRT machinery to the site of viral budding. In T cells (left panel), viral assembly and release occur at the plasma membrane, whereas in macrophages (center) HIV particles accumulate in late endosomes and MVBs. In DCs (right panel), HIV undergoes receptor-mediated endocytosis after binding to DC-SIGN and is recycled to the cell surface. Although the vesicular compartments involved have not been identified, macrophages and DCs may share a mechanism for releasing HIV particles upon contact with T lymphocytes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172700&req=5

fig2: Mimicry of Hrs function by HIV Gag. The normal function of Hrs, shown in the left panel, is to recruit Tsg101 and the ESCRT-I complex for sorting ubiquitinated (Ub) cargo into the MVB. During HIV infection, HIV Gag mimics Hrs and redirects the ESCRT machinery to the site of viral budding. In T cells (left panel), viral assembly and release occur at the plasma membrane, whereas in macrophages (center) HIV particles accumulate in late endosomes and MVBs. In DCs (right panel), HIV undergoes receptor-mediated endocytosis after binding to DC-SIGN and is recycled to the cell surface. Although the vesicular compartments involved have not been identified, macrophages and DCs may share a mechanism for releasing HIV particles upon contact with T lymphocytes.
Mentions: The new studies have approached the problem of how ESCRT-I is recruited to the site of MVB formation from different angles. Emr and colleagues have used fluorescently tagged proteins to examine their relationship in yeast (Katzmann et al., 2003). They show that GFP-tagged Vps27p colocalizes with DS-Red–tagged FYVE domain of EEA1, an early endosomal marker, and that this requires the FYVE domain of Vps27p (Fig. 1). Moreover, the protein was diffusely distributed in the cytoplasm in PI 3-kinase–deficient vps34 mutant cells, consistent with a requirement for PI(3)P in the recruitment of Vps27p to endosomes (Katzmann et al., 2003). Vps23p was coprecipitated with Vps27p from membrane fractions, but not soluble fractions, of cells transfected with epitope-tagged versions of both proteins, suggesting a direct interaction between Vps27p and ESCRT-I only on endosomal membranes. This interaction did not require either the UIM or the conserved VHS domain of unknown function in the NH2-terminal part of Vps27p. GFP-Vps27p was localized to endosomal structures in a Vps23p-deficient strain, but Vps23p-GFP was diffusely distributed in the cytoplasm in the absence of either Vps27p or Vps34p (Katzmann et al., 2003). These results suggest that Vps27 acts upstream of Vps23, recruiting it to the endosomal limiting membrane once it is activated due to interaction with cargo protein (Fig. 2). Targeting of Vps23p-GFP to endosomal membranes required expression of Vps27p with an intact P/Q-rich COOH-terminal domain, including PSDP and PTVP sequences resembling those in retroviral L domains.

Bottom Line: To efficiently bud off from infected cells, HIV and other enveloped viruses hijack the host cellular machinery that is normally involved in vacuolar protein sorting and multivesicular body (MVB) biogenesis.The HIV Gag protein mimics hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a modular adaptor protein that links membrane cargo recognition to its degradation after delivery to MVBs.In contrast to T cells, where HIV budding occurs at the plasma membrane, virus buds into vacuoles of macrophages, a process that may facilitate its spread within the infected host.

View Article: PubMed Central - PubMed

Affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
To efficiently bud off from infected cells, HIV and other enveloped viruses hijack the host cellular machinery that is normally involved in vacuolar protein sorting and multivesicular body (MVB) biogenesis. The HIV Gag protein mimics hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a modular adaptor protein that links membrane cargo recognition to its degradation after delivery to MVBs. In contrast to T cells, where HIV budding occurs at the plasma membrane, virus buds into vacuoles of macrophages, a process that may facilitate its spread within the infected host.

Show MeSH
Related in: MedlinePlus