scholarly journals Interactions of HIV-1 Nef with the μ Subunits of Adaptor Protein Complexes 1, 2, and 3: Role of the Dileucine-Based Sorting Motif

Virology ◽  
2000 ◽  
Vol 271 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Heather M. Craig ◽  
Thipparthi R. Reddy ◽  
Nanette L. Riggs ◽  
Philip P. Dao ◽  
John C. Guatelli
Keyword(s):  
Protein Complexes ◽  
Adaptor Protein ◽  
Sorting Motif ◽  
Hiv 1

scholarly journals S-Palmitoylation determines TMEM55B-dependent positioning of lysosomes

2021 ◽  
Author(s):  
Sönke Rudnik ◽  
Saskia Heybrock ◽  
Paul Saftig ◽  
Markus Damme
Keyword(s):  
Molecular Motors ◽  
Protein Complexes ◽  
Critical Role ◽  
Adaptor Protein ◽  
Retrograde Transport ◽  
Microtubule Motors ◽  
Lysosomal Sorting ◽  
Sorting Motif ◽  
Spatio Temporal

The spatio-temporal cellular distribution of lysosomes depends on active transport mainly driven by microtubule-motors such as kinesins and dynein. Different protein complexes attach these molecular motors to their vesicular cargo: TMEM55B, as an integral lysosomal membrane protein, is a component of such a complex mediating the retrograde transport of lysosomes by establishing an interaction with the cytosolic scaffold protein JIP4 and dynein/dynactin. Here we show that TMEM55B and its paralog TMEM55A are S-palmitoylated proteins and lipidated at multiple cysteine-residues. Mutation of all cysteines in TMEM55B prevents S-palmitoylation and causes the retention of the mutated protein in the Golgi-apparatus. Consequently, non-palmitoylated TMEM55B is no longer able to modulate lysosomal positioning and the perinuclear clustering of lysosomes. Additional mutagenesis of the dileucine-based lysosomal sorting motif in non-palmitoylated TMEM55B leads to partial missorting to the plasma membrane instead of retention in the Golgi, implicating a direct effect of S-palmitoylation on the adaptor-protein-dependent sorting of TMEM55B. Our data suggest a critical role of S-palmitoylation on the trafficking of TMEM55B and TMEM55B-dependent lysosomal positioning.

scholarly journals Subunit H of the V-ATPase Involved in Endocytosis Shows Homology to β-Adaptins

2002 ◽  
Vol 13 (6) ◽  
pp. 2045-2056 ◽  
Author(s):  
Matthias Geyer ◽  
Oliver T. Fackler ◽  
B. Matija Peterlin
Keyword(s):  
Intracellular Trafficking ◽  
Protein Complexes ◽  
Consensus Sequence ◽  
Transmembrane Proteins ◽  
Adaptor Protein ◽  
Regulatory Subunit ◽  
Protein Fold ◽  
Intracellular Compartments ◽  
Sorting Motif ◽  
Hiv 1

The vacuolar ATPase (V-ATPase) is a multisubunit enzyme that facilitates the acidification of intracellular compartments in eukaryotic cells and plays an important role in receptor-mediated endocytosis, intracellular trafficking processes, and protein degradation. In this study we show that the C-terminal fragment of 350 residues of the regulatory subunit H (V1H) of the V-ATPase shares structural and functional homologies with the β-chains of adaptor protein complexes. Moreover, the fragment is similar to a region in the β-subunit of COPI coatomer complexes, which suggests the existence of a shared domain in these three different families of proteins. For β-adaptins, this fragment binds to cytoplasmic di-leucine–based sorting motifs such as in HIV-1 Nef that mediate endocytic trafficking. Expression of this fragment in cells blocks the internalization of transmembrane proteins, which depend on di-leucine–based motifs, whereas mutation of the consensus sequence GEY only partly diminishes the recognition of the sorting motif. Based on recent structural analysis, our results suggest that the di-leucine-binding domain consists of a HEAT or ARM repeat protein fold.

scholarly journals Interactions with Commensal and Pathogenic Bacteria Induce HIV-1 Latency in Macrophages through Altered Transcription Factor Recruitment to the LTR

2021 ◽  
Author(s):  
Gregory A. Viglianti ◽  
Vicente Planelles ◽  
Timothy M. Hanley
Keyword(s):  
Adaptor Protein ◽  
Type I ◽  
Major Barrier ◽  
E Coli ◽  
Tissue Microenvironment ◽  
Viral Spread ◽  
Latent Hiv ◽  
Hiv 1

Macrophages are infected by HIV-1 in vivo and contribute to both viral spread and pathogenesis. Recent human and animal studies suggest that HIV-1-infected macrophages serve as a reservoir that contributes to HIV-1 persistence during anti-retroviral therapy. The ability of macrophages to serve as persistent viral reservoirs is likely influenced by the local tissue microenvironment, including interactions with pathogenic and commensal microbes. Here we show that the sexually transmitted pathogen Neisseria gonorrhoeae (GC) and the gut-associated microbe Escherichia coli (E. coli), which encode ligands for both Toll-like receptor 2 (TLR2) and TLR4, repressed HIV-1 replication in macrophages and thereby induced a state reminiscent of viral latency. This repression was mediated by signaling through TLR4 and the adaptor protein TRIF and was associated with increased production of type I interferons. Inhibiting TLR4 signaling, blocking type 1 interferon, or knocking-down TRIF reversed LPS- and GC-mediated repression of HIV-1. Finally, the repression of HIV-1 in macrophages was associated with the recruitment of interferon regulatory factor 8 (IRF8) to the interferon stimulated response element (ISRE) downstream of the 5’ HIV-1 long terminal repeat (LTR). Our data indicate that IRF8 is responsible for repression of HIV-1 replication in macrophages in response to TRIF-dependent signaling during GC and E. coli co-infection. These findings highlight the potential role of macrophages as HIV-1 reservoirs as well as the role of the tissue microenvironment and co-infections as modulators of HIV-1 persistence. IMPORTANCE The major barrier toward the eradication of HIV-1 infection is the presence of a small reservoir of latently infected cells, which include CD4+ T cells and macrophages that escape immune-mediated clearance and the effects of anti-retroviral therapy. There remain crucial gaps in our understanding of the molecular mechanisms that lead to transcriptionally silent or latent HIV-1 infection of macrophages. The significance of our research is in identifying microenvironmental factors, such as commensal and pathogenic microbes, that can contribute to the establishment and maintenance of latent HIV-1 infection in macrophages. It is hoped that identifying key processes contributing to HIV-1 persistence in macrophages may ultimately lead to novel therapeutics to eliminate latent HIV-1 reservoirs in vivo.

scholarly journals The Mechanism of Budding of Retroviruses from Cell Membranes

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Andrew Pincetic ◽  
Jonathan Leis
Keyword(s):  
Protein Complexes ◽  
Cellular Protein ◽  
Multivesicular Bodies ◽  
Escrt Machinery ◽  
Immunodeficiency Virus ◽  
Cellular Machinery ◽  
Avian Sarcoma ◽  
Hiv 1

Retroviruses have evolved a mechanism for the release of particles from the cell membrane that appropriates cellular protein complexes, referred to as ESCRT-I, -II, -III, normally involved in the biogenesis of multivesicular bodies. Three different classes of late assembly (L) domains encoded in Gag, with core sequences of PPXY, PTAP, and YPXL, recruit different components of the ESCRT machinery to form a budding complex for virus release. Here, we highlight recent progress in identifying the role of different ESCRT complexes in facilitating budding, ubiquitination, and membrane targeting of avian sarcoma and leukosis virus (ASLV) and human immunodeficiency virus, type 1 (HIV-1). These findings show that retroviruses may adopt parallel budding pathways by recruiting different host factors from common cellular machinery for particle release.

scholarly journals The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry

2012 ◽  
Vol 23 (12) ◽  
pp. 2253-2263 ◽  
Author(s):  
Mónica Gordón-Alonso ◽  
Vera Rocha-Perugini ◽  
Susana Álvarez ◽  
Olga Moreno-Gonzalo ◽  
Ángeles Ursa ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Adaptor Protein ◽  
Viral Receptor ◽  
Actin Remodeling ◽  
Cellular Processes ◽  
Immunodeficiency Virus ◽  
Viral Nucleocapsid ◽  
Hiv 1

Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4+T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP2) production, which are needed for successful HIV infection. We show that syntenin-1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV-1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP2accumulation is increased in syntenin-1–depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP2production, and the dynamics of HIV-1 entry.

scholarly journals HIV-1 Nef Stabilizes the Association of Adaptor Protein Complexes with Membranes

2002 ◽  
Vol 278 (10) ◽  
pp. 8725-8732 ◽  
Author(s):  
Katy Janvier ◽  
Heather Craig ◽  
Douglas Hitchin ◽  
Ricardo Madrid ◽  
Nathalie Sol-Foulon ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Adaptor Protein ◽  
Hiv 1

scholarly journals Interactions with Commensal and Pathogenic Bacteria Induce HIV-1 Latency in Macrophages through Altered Transcription Factor Recruitment to the LTR

2020 ◽  
Author(s):  
Gregory A. Viglianti ◽  
Vicente Planelles ◽  
Timothy M. Hanley
Keyword(s):  
Adaptor Protein ◽  
Type I ◽  
Major Barrier ◽  
E Coli ◽  
Tissue Microenvironment ◽  
Viral Spread ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACTMacrophages are infected by HIV-1 in vivo and contribute to both viral spread and pathogenesis. Recent human and animal studies suggest that HIV-1-infected macrophages serve as a reservoir that contributes to HIV-1 persistence during anti-retroviral therapy. The ability of macrophages to serve as persistent viral reservoirs is likely influenced by the local tissue microenvironment, including interactions with pathogenic and commensal microbes. Here we show that the sexually transmitted pathogen Neisseria gonorrhoeae (GC) and the gut-associated microbe Escherichia coli (E. coli), which encode ligands for both Toll-like receptor 2 (TLR2) and TLR4, repressed HIV-1 replication in macrophages and thereby induced a state reminiscent of viral latency. This repression was mediated by signaling through TLR4 and the adaptor protein TRIF and was associated with increased production of type I interferons. Inhibiting TLR4 signaling, blocking type 1 interferon, or knocking-down TRIF reversed LPS- and GC-mediated repression of HIV-1. Finally, the repression of HIV-1 in macrophages was associated with the recruitment of interferon regulatory factor 8 (IRF8) to the interferon stimulated response element (ISRE) downstream of the 5′ HIV-1 long terminal repeat (LTR). Our data indicate that IRF8 is responsible for repression of HIV-1 replication in macrophages in response to TRIF-dependent signaling during GC and E. coli co-infection. These findings highlight the potential role of macrophages as HIV-1 reservoirs as well as the role of the tissue microenvironment and co-infections as modulators of HIV-1 persistence.IMPORTANCEThe major barrier toward the eradication of HIV-1 infection is the presence of a small reservoir of latently infected cells, which include CD4+ T cells and macrophages that escape immune-mediated clearance and the effects of anti-retroviral therapy. There remain crucial gaps in our understanding of the molecular mechanisms that lead to transcriptionally silent or latent HIV-1 infection of macrophages. The significance of our research is in identifying microenvironmental factors, such as commensal and pathogenic microbes, that can contribute to the establishment and maintenance of latent HIV-1 infection in macrophages. It is hoped that identifying key processes contributing to HIV-1 persistence in macrophages may ultimately lead to novel therapeutics to eliminate latent HIV-1 reservoirs in vivo.

scholarly journals Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Xiaofei Jia ◽  
Erin Weber ◽  
Andrey Tokarev ◽  
Mary Lewinski ◽  
Maryan Rizk ◽  
...  
Keyword(s):  
Cell Surface ◽  
Membrane Trafficking ◽  
Protein Complex ◽  
Adaptor Protein ◽  
Structural Basis ◽  
Host Proteins ◽  
Viral Protein U ◽  
Sorting Motif ◽  
Clathrin Adaptor ◽  
Hiv 1

BST2/tetherin, an antiviral restriction factor, inhibits the release of enveloped viruses from the cell surface. Human immunodeficiency virus-1 (HIV-1) antagonizes BST2 through viral protein u (Vpu), which downregulates BST2 from the cell surface. We report the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1). This, together with our biochemical and functional validations, reveals how Vpu hijacks the AP1-dependent membrane trafficking pathways to mistraffick BST2. Vpu mimics a canonical acidic dileucine-sorting motif to bind AP1 in the cytosol, while simultaneously interacting with BST2 in the membrane. These interactions enable Vpu to build on an intrinsic interaction between BST2 and AP1, presumably causing the observed retention of BST2 in juxtanuclear endosomes and stimulating its degradation in lysosomes. The ability of Vpu to hijack AP-dependent trafficking pathways suggests a potential common theme for Vpu-mediated downregulation of host proteins.

scholarly journals Mechanism for Removal of Tumor Necrosis Factor Receptor 1 from the Cell Surface by the Adenovirus RIDα/β Complex

2005 ◽  
Vol 79 (21) ◽  
pp. 13606-13617 ◽  
Author(s):  
Y. Rebecca Chin ◽  
Marshall S. Horwitz
Keyword(s):  
Plasma Membrane ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Sorting Motif ◽  
Interfering Rna ◽  
Necrosis Factor

ABSTRACT Proteins encoded in adenovirus early region 3 have important immunoregulatory properties. We have recently shown that the E3-10.4K/14.5K (RIDα/β) complex downregulates tumor necrosis factor receptor 1 (TNFR1) expression at the plasma membrane. To study the role of the RIDβ tyrosine sorting motif in the removal of surface TNFR1, tyrosine 122 on RIDβ was mutated to alanine or phenylalanine. Both RIDβ mutations not only abolished the downregulation of surface TNFR1 but paradoxically increased surface TNFR1 levels. RID also downregulates other death receptors, such as FAS; however, surface FAS expression was not increased by RIDβ mutants, suggesting that regulation of TNFR1 and that of FAS by RID are mechanistically different. In the mixing experiments, the wild-type (WT) RID-mediated TNFR1 downregulation was partially inhibited in the presence of RIDβ mutants, indicating that the mutants compete for TNFR1 access. Indeed, an association between RIDβ and TNFR1 was shown by coimmunoprecipitation. In contrast, the mutants did not affect the WT RID-induced downregulation of FAS. These differential effects support a model in which RID associates with TNFR1 on the plasma membrane, whereas RID probably associates with FAS in a cytoplasmic compartment. By using small interfering RNA against the μ2 subunit of adaptor protein 2, dominant negative dynamin construct K44A, and the lysosomotropic agents bafilomycin A1 and ammonium chloride, we also demonstrated that surface TNFR1 was internalized by RID by a clathrin-dependent process involving μ2 and dynamin, followed by degradation of TNFR1 via an endosomal/lysosomal pathway.

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