Bst‐2/HM1.24 Is a Raft‐Associated Apical Membrane Protein with an Unusual Topology

Kupzig, Sabine; Korolchuk, Viktor I.; Rollason, Ruth; Sugden, Anna; Wilde, Andrew; Banting, George

doi:10.1034/j.1600-0854.2003.00129.x

Cited by 393 publications

(610 citation statements)

References 57 publications

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“…From results presented here, it is reasonable to propose that up-regulated STAT1 may enhance IFI27 and OAS1 expression in breast tumors. The function of BST2 also remains unknown but may be important in sorting membrane and secreted proteins in the Golgi apparatus, localized on both cell surface and intracellular compartments (23). The expression of BST2 was predominantly specific for type I IFN-producing cells in the naïve mouse and was up-regulated in most cell types after stimulation with type I IFNs or IFN-␥ (24).…”

Section: Discussionmentioning

confidence: 99%

Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

Cheon

Stark

2009

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

271

259

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In normal human cells treated with interferons (IFNs), the concentration of tyrosine-phosphorylated STAT1 (YP-STAT1), which drives the expression of a large number of genes, increases quickly but then decreases over a period of several hours. Because the STAT1 gene is activated by YP-STAT1, IFNs stimulate a large increase in the concentration of unphosphorylated STAT1 (U-STAT1) that persists for several days. To test the significance of high U-STAT1 expression, we increased its concentration exogenously in the absence of IFN treatment. In response, the expression of many immune regulatory genes (e.g., IFI27, IFI44, OAS, and BST2) was increased. In human fibroblasts or mammary epithelial cells treated with low concentrations of IFN-␤ or IFN-␥, the expression of the same genes increased after 6 h and continued to increase after 48 or 72 h, long after the concentration of YP-STAT1 had returned to basal levels. Consistent with its activity as a transcription factor, most U-STAT1 was present in the nuclei of these cells before IFN treatment, and the fraction in nuclei increased 48 h after treatment with IFN. We conclude that the nuclear U-STAT1 that accumulates in response to IFNs maintains or increases the expression of a subset of IFN-induced genes independently of YP-STAT1, and that many of the induced proteins are involved in immune regulation. Their signaling pathways are mediated by the sequential phosphorylation of Janus family kinases (JAKs) and STATs. Type I IFNs phosphorylate STATs 1 and 2, which form IFN-stimulated gene factor-3 (ISGF-3), a ternary complex that also includes IFN response factor-9 (IRF9). IFN-␥ induces the phosphorylation of STAT1, which forms STAT1 homodimers. These activated transcription factors translocate into the nucleus, where they bind to distinct conserved sequences in the promoters of target genes. However, recent studies have shown that IFN signaling is much more complex (2). IFNs activate several different kinases in addition to the JAKs, other STATs in addition to STAT1 and STAT2, and even other transcription factors (3-9).Our previous work has shown that STAT1 drives the constitutive expression of some genes without phosphorylation (10, 11). For example, the complex of unphosphorylated STAT1 (U-STAT1) and IRF1 mediates the constitutive expression of the low-molecular mass polypeptide 2 (LMP2) gene (11). Similarly, Cui et al. (12) have shown that unphosphorylated STAT6 cooperates with p300 to increase transcription of the cyclooxygenase-2 gene. Initially, unphosphorylated STATs were considered to be latent transcription factors in the cytoplasm, entering the nucleus to induce gene expression only in response to cytokine stimulation. However, consistent with our previous results, STAT1 and STAT3 have been found to be present in nuclei independently of tyrosine phosphorylation, in a cell type-specific manner, and the nuclear import mechanism of U-STAT1 is completely distinct from that of phosphorylated STAT1 (13, 14). The nuclear import of tyrosinephosphorylated STAT1 dimers dep...

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Section: Discussionmentioning

confidence: 99%

Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

Cheon

Stark

2009

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

271

259

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“…1). Removal of the anchor does not affect association of BST‐2 with the cell membrane; however, lipid raft localization of BST‐2 is lost 9.…”

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confidence: 94%

“…Furthermore, BST‐2 ectodomain is post‐translationally modified by N‐linked glycosylation of two asparagine residues at positions 65 and 92 9, 11, 21. Although the function of BST‐2 glycosylation for inhibition of virus release is unclear 11, 22, this post‐translational modification is important for proper folding and trafficking of BST‐2 through the endoplasmic reticulum (ER) and the Golgi 23.…”

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confidence: 99%

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The role of BST‐2/Tetherin in host protection and disease manifestation

Mahauad‐Fernandez

Okeoma

2015

Immunity, Inflammation and Disease

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Host cells respond to viral infections by activating immune response genes that are not only involved in inflammation, but may also predispose cells to cancerous transformation. One such gene is BST‐2, a type II transmembrane protein with a unique topology that endows it tethering and signaling potential. Through this ability to tether and signal, BST‐2 regulates host response to viral infection either by inhibiting release of nascent viral particles or in some models inhibiting viral dissemination. However, despite its antiviral functions, BST‐2 is involved in disease manifestation, a function linked to the ability of BST‐2 to promote cell‐to‐cell interaction. Therefore, modulating BST‐2 expression and/or activity has the potential to influence course of disease.

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“…Bst-2 is a 30-to 36-kDa type II transmembrane protein consisting of 180 aa (27). The protein has an unusual topology in that it has both an N-terminal transmembrane domain and a C-terminal glycosylphosphatidylinositol (GPI) anchor (28). Bst-2 associates with lipid rafts at the cell surface and was identified on internal membranes, presumably the trans-Golgi network (28).…”

Section: Hiv-1 Vpu Enhances the Release Of Virions From Infected Cellsmentioning

confidence: 99%

Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion

Miyagi

Andrew

Kao

et al. 2009

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

206

281

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HIV-1 Vpu enhances the release of virions from infected cells. Recent work identified Bst-2/CD317/tetherin as a host factor whose inhibitory activity on viral release is counteracted by Vpu. A current working model proposes that Bst-2 inhibits virus release by tethering viral particles to the cell surface. Here, we analyzed endogenous Bst-2 with respect to its effect on virus release from HeLa cells, T cells, and macrophages. We noted significant cell type-dependent variation in Bst-2 expression. Vpu caused a reduction in Bst-2 expression in transfected HeLa cells and long-term infected macrophages. However, Vpu expression did not result in cell surface down-modulation of Bst-2 or a reduction in intracellular Bst-2 expression in CEMx174 or H9 cells, yet virus replication in these cells was Vpu-responsive. Surprisingly, Bst-2 was undetectable in cell-free virions that were recovered from the surface of HeLa cells by physical shearing, suggesting that a tethering model may not explain all of the functional properties of Bst-2. Taken together we conclude that enhancement of virus release by Vpu does not, at least in CEMx174 and H9 cells, require cell surface down-modulation or intracellular depletion of Bst-2, nor does it entail exclusion of Bst-2 from viral particles.

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Bst‐2/HM1.24 Is a Raft‐Associated Apical Membrane Protein with an Unusual Topology

Cited by 393 publications

References 57 publications

Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

The role of BST‐2/Tetherin in host protection and disease manifestation

Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion

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