A CD63 Mutant Inhibits T‐cell Tropic Human Immunodeficiency Virus Type 1 Entry by Disrupting CXCR4 Trafficking to the Plasma Membrane

Yoshida, Takeshi; Kawano, Yoshiaki; Sato, Kei; Ando, Yoshinori; Aoki, Jun; Miura, Yoshiharu; Komano, Jun; Tanaka, Yuetsu; Koyanagi, Yoshio

doi:10.1111/j.1600-0854.2007.00700.x

Cited by 66 publications

(66 citation statements)

References 46 publications

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“…It is possible, however, that endogenous GBA1 exerts its anti-EV71 effects through other mechanisms for a slight downregulation of cell surface SCARB2 expression. Few intrinsic negative regulators of viral infection have been reported to act through the attenuation of receptor trafficking [25]. To the best of our knowledge, our finding is unique in this regard.…”

Section: Discussioncontrasting

confidence: 44%

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

Nakata

Takeda

Tanaka

et al. 2017

Journal of General Virology

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Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD). EV71 causes fever, rash, diarrhoea and, in some cases, acute encephalopathy/encephalitis, which can be fatal. No specific treatment is currently available for EV71 infection. Here, we conducted a cDNA library screen and identified acid b-glucosidase 1 (GBA1; also known as bglucocerebrosidase) as an EV71 resistance factor. The anti-EV71 function of GBA1 was verified by gene transduction and knockdown experiments. Cerezyme, a molecular drug used to treat Gaucher's disease and having recombinant human GBA1 as the active ingredient, protected against EV71 infection. The anti-EV71 activity of GBA1 was bimodal: endogenous GBA1 restricted cell surface expression levels of scavenger receptor class B, member 2 (SCARB2), also known as lysosomal integral membrane protein 2 (LIMP-2), and exogenous recombinant GBA1 interfered with EV71 to interact with SCARB2 outside the cell. Thus, our findings suggest that GBA1 may represent a novel molecular target for the treatment of EV71 infection.

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Section: Discussioncontrasting

confidence: 44%

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

Nakata

Takeda

Tanaka

et al. 2017

Journal of General Virology

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“…4B) explain why the repression of virus-cell fusion was not observed previously. Finally, we asked whether the fusion-preventive functions of tetraspanins in producer cells (described in this report) were independent of their entry-inhibiting activities in target cells (14,18,47,51). The data presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, tetraspanins on uninfected (target) cells inhibit HIV-1-induced cell-cell fusion (14). This fusion regulation is likely due to interactions of CD9 and CD81 with CD4 and coreceptors at the surface of target cells, though the tetraspanin CD63 has also been implicated in the trafficking of CXCR4 to the plasma membrane (51).…”

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confidence: 99%

Formation of Syncytia Is Repressed by Tetraspanins in Human Immunodeficiency Virus Type 1-Producing Cells

Weng¹,

Krementsov

Khurana³

et al. 2009

J Virol

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In vitro propagation studies have established that human immunodeficiency virus type 1 (HIV-1) is most efficiently transmitted at the virological synapse that forms between producer and target cells. Despite the presence of the viral envelope glycoprotein (Env) and CD4 and chemokine receptors at the respective surfaces, producer and target cells usually do not fuse with each other but disengage after the viral particles have been delivered, consistent with the idea that syncytia, at least in vitro, are not required for HIV-1 spread. Here, we tested whether tetraspanins, which are well known regulators of cellular membrane fusion processes that are enriched at HIV-1 exit sites, regulate syncytium formation. We found that overexpression of tetraspanins in producer cells leads to reduced syncytium formation, while downregulation has the opposite effect. Further, we document that repression of Env-induced cell-cell fusion by tetraspanins depends on the presence of viral Gag, and we demonstrate that fusion repression requires the recruitment of Env by Gag to tetraspanin-enriched microdomains (TEMs). However, sensitivity to fusion repression by tetraspanins varied for different viral strains, despite comparable recruitment of their Envs to TEMs. Overall, these data establish tetraspanins as negative regulators of HIV-1-induced cell-cell fusion, and they start delineating the requirements for this regulation.The envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is incorporated into released virus particles and enables the virus to attach to and fuse with target cells in order to initiate the infectious cycle. Before Env mediates the fusion of viral and cellular membranes, i.e., while it is still incorporated in the plasma membrane of the infected cell, it drives the adhesion between virus producer cell and target cells, which gives rise to the formation of the so-called virological synapse (VS) (21,24,35,36). The VS shares certain characteristics with the immunological synapse, including an accumulation of specific cellular membrane proteins and lipids (see, e.g., reference 5), and it provides efficient and secure transfer of virus particles from infected to uninfected cells (8). Importantly, the two adhering cells, like the pre-and postsynaptic cells that form an immunological synapse, typically do not fuse during such cell-to-cell transfer events. At first glance this seems surprising, as HIV-1 Env, unlike many other viral envelope proteins, can induce membrane fusion at physiological pH. Also, adhesion of producer and target cell, which can be initiated when the uropod of the infected cell contacts the uninfected cell (8), followed by reorganization of the cytoskeleton (25) and formation of full-fledged synapses, can extend over minutes (see, e.g., reference 20). This process should allow enough time to trigger cell-cell fusion. However, it is now well established that newly synthesized Env is efficiently internalized upon its arrival at the host cell plasma membrane, unless it is recruited ...

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“…Although we were not able to show clear results proving IL-21-induced CXCR4 downregulation in centrocytes in vivo, IL-21 has a potential to control CXCR4 downregulation not only on activated B cells but also on GC B cells. Second, we showed that CD63, which traffics CXCR4 to late endosome in CD4 T cells (17), downregulates CXCR4 expression on activated B cells. The amount of CD63 mRNA was inversely correlated with that of Bcl6 mRNA in GC B cells, and the amount of CD63 protein was strikingly augmented in activated Bcl6 2/2 B cells.…”

Section: Discussionmentioning

confidence: 78%

“…The various endocytosis-related molecules including GRK6, b-arrestin2 (Arrb2), and AIP4 are inducible in CD4 T cells for the clathrin-dependent internalization of CXCR4 (13)(14)(15)(16). Of the exocytosis-related molecules, CD63, a ubiquitously expressed tetraspanin, has been identified as a negative regulator of CXCR4 exocytosis in CD4 T cells (17,18). CD63 interacts with CXCR4 directly through the N-linked glycans portion of CD63.…”

mentioning

confidence: 99%

CXCR4 Expression on Activated B Cells Is Downregulated by CD63 and IL-21

Yoshida

Kitayama

Arima

et al. 2011

The Journal of Immunology

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CXCR4 expression is critical for localization of centroblasts in the dark zone of germinal centers (GCs), and centrocytes downregulate CXCR4 and thus leave the dark zone to reside in the light zone. However, mechanisms governing CXCR4 downregulation on centrocytes are not known. In this study, we show that the amount of intracellular CXCR4 in centroblasts was similar to that in centrocytes, suggesting differential control of CXCR4 protein expression in these GC B cells. Restimulation of activated B cells with IL-21, which is a major cytokine produced by T follicular helper cells, accelerated CXCR4 internalization by inducing endocytosis-related GRK6 expression. Although CXCR4 expression was downregulated on GC B cells by IL-21 stimulation, CXCR4low centrocytes developed in the spleens of IL-21R–deficient mice, suggesting other mechanisms for downregulation. The level of CD63 (which recruits CXCR4 to late endosome in CD4 T cells) in centrocytes was more than that in centroblasts and was strikingly elevated in activated Bcl6-deficient B cells. Bcl6, a transcriptional repressor, was detected on the chromatin of the CD63 gene in resting B cells, therefore CD63 is a molecular target of Bcl6. Downregulation of CD63 mRNA in activated Bcl6-deficient B cells by small interfering RNA upregulated CXCR4 expression on the B cells. Furthermore, addition of Bcl6 inhibitor to activated B cell cultures increased CD63 mRNA expression in (and downregulated CXCR4 expression on) those activated B cells. Thus, CXCR4 can be downregulated on activated B cells by IL-21–induced endocytosis and CD63-mediated endosomal recruitment, and these mechanisms may contribute to downregulation of CXCR4 on centrocytes.

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A CD63 Mutant Inhibits T‐cell Tropic Human Immunodeficiency Virus Type 1 Entry by Disrupting CXCR4 Trafficking to the Plasma Membrane

Cited by 66 publications

References 46 publications

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

Formation of Syncytia Is Repressed by Tetraspanins in Human Immunodeficiency Virus Type 1-Producing Cells

CXCR4 Expression on Activated B Cells Is Downregulated by CD63 and IL-21

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