Glycans, galectins, and HIV-1 infection Sato, Sachiko; Ouellet, Michel; St-Pierre, Christian ...
Annals of the New York Academy of Sciences,
April 2012, Letnik:
1253, Številka:
1
Journal Article
Recenzirano
During sexual transmission, HIV‐1 must overcome physiological barriers to establish a founder cell population. Viral adhesion represents a bottleneck for HIV‐1 propagation that the virus widens by ...exploiting some specific host factors. Recognition of oligomannosyl glycans of gp120 by C‐type lectins is one such example. Recent works suggest that complex glycans of gp120 are recognized by another host lectin, galectin‐1. This interaction results in rapid association of HIV‐1 to susceptible cells and facilitates infection. The peculiar presentation of complex glycans on gp120 seems to impart specificity for galectin‐1, as another member of the same family, galectin‐3, is unable to bind gp120 or enhance HIV‐1 infection. Other studies have shown that galectin‐9 could also increase HIV‐1 infectivity but via an indirect mechanism. Thus, current research suggests that galectins play various roles in HIV‐1 pathogenesis. Drug discovery approaches targeting host lectins at early steps could benefit the current arsenal of antiretrovirals.
Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase ...(TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8(+) T cell proliferation. Consistent with this, T cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8(+) T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising.
The Leishmania tarentolae Parrot-TarII strain genome sequence was resolved to an average 16-fold mean coverage by next-generation DNA sequencing technologies. This is the first non-pathogenic to ...humans kinetoplastid protozoan genome to be described thus providing an opportunity for comparison with the completed genomes of pathogenic Leishmania species. A high synteny was observed between all sequenced Leishmania species. A limited number of chromosomal regions diverged between L. tarentolae and L. infantum, while remaining syntenic to L. major. Globally, >90% of the L. tarentolae gene content was shared with the other Leishmania species. We identified 95 predicted coding sequences unique to L. tarentolae and 250 genes that were absent from L. tarentolae. Interestingly, many of the latter genes were expressed in the intracellular amastigote stage of pathogenic species. In addition, genes coding for products involved in antioxidant defence or participating in vesicular-mediated protein transport were underrepresented in L. tarentolae. In contrast to other Leishmania genomes, two gene families were expanded in L. tarentolae, namely the zinc metallo-peptidase surface glycoprotein GP63 and the promastigote surface antigen PSA31C. Overall, L. tarentolae's gene content appears better adapted to the promastigote insect stage rather than the amastigote mammalian stage.
Receptor tyrosine phosphatase sigma (RPTPσ) plays an important role in the regulation of axonal outgrowth and neural regeneration. Recent studies have identified two RPTPσ ligands, chondroitin ...sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPG), which can modulate RPTPσ activity by affecting its dimerization status. Here, we developed a split luciferase assay to monitor RPTPσ dimerization in living cells. Using this system, we demonstrate that heparin, an analog of heparan sulfate, induced the dimerization of RPTPσ, whereas chondroitin sulfate increased RPTPσ activity by inhibiting RPTPσ dimerization. Also, we generated several novel RPTPσ IgG monoclonal antibodies, to identify one that modulates its activity by inducing/stabilizing dimerization in living cells. Lastly, we demonstrate that this antibody promotes neurite outgrowth in SH-SY5Y cells. In summary, we demonstrated that the split luciferase RPTPσ activity assay is a novel high-throughput approach for discovering novel RPTPσ modulators that can promote axonal outgrowth and neural regeneration.
Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none ...of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS) is expressed specifically on pDCs. Surface PTPRS was rapidly downregulated after pDC activation, and only PTPRS− pDCs produced IFN-α. Antibody-mediated PTPRS crosslinking inhibited pDC activation, whereas PTPRS knockdown enhanced IFN response in a pDC cell line. Similarly, murine Ptprs and the homologous receptor phosphatase Ptprf were specifically co-expressed in murine pDCs. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background were associated with enhanced IFN response of pDCs, leukocyte infiltration in the intestine and mild colitis. Thus, PTPRS represents an evolutionarily conserved pDC-specific inhibitory receptor, and is required to prevent spontaneous IFN production and immune-mediated intestinal inflammation.
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•Human pDCs specifically express receptor protein tyrosine phosphatase PTPRS•Murine pDCs specifically express Ptprs and the homologous phosphatase Ptprf•Ptprs inhibits interferon production by murine and human pDCs•Combined loss of Ptprs and Ptprf cause pDC hyperactivation and mild colitis
Plasmacytoid dendritic cells (pDCs) express unique receptors that inhibit their interferon-producing capacity, yet none of the known receptors are conserved in evolution. Reizis and colleagues identify protein tyrosine phosphatase sigma (PTPRS) as an inhibitory receptor on human and murine pDCs that prevents pDC hyperactivation and intestinal inflammation.
The research has long assumed that the perception of career plateauing triggers negative affective and behavioral reactions (i.e., normal effect perspective), and that the models hold at the ...between-person and within-person levels. However, some scholars suggest that the affective and behavioral engagement of employees may also affect their career experiences (i.e., reverse relationship perspective), and caution us not to infer homology across levels. To test these competing perspectives, we analyzed 1227 observations from three longitudinal survey waves conducted over 42 months with 409 employees of a Canadian financial/insurance company. The results indicate that higher than usual occasion reports of content plateauing were related to decreased affective commitment and OCB, while hierarchical plateauing perceptions were only negatively related at the between-level to affective commitment. This study found support for an inverse association between OCB and content plateauing, such that lower than usual reports of OCB were related to increased perceptions of content plateauing (reverse relationship perspective). Across times, OCB was found to be a more proximal predictor of content plateauing than affective commitment. This study contributes to the literature on career plateauing by demonstrating the dynamic nature of content plateauing perceptions and the limited role of hierarchical plateauing when the role of content plateau and time is considered.
•Content plateauing reduces affective commitment to organization and OCB.•Affective commitment and OCB reduce content plateauing over time.•Affective commitment is associated to an increase of OCB over time.•Content plateauing elicits more negative reactions than hierarchical plateauing.
The dynamic interplay between dendritic cells (DCs) and human immunodeficiency virus type-1 (HIV-1) is thought to result in viral dissemination and evasion of antiviral immunity. Although initial ...observations suggested that the C-type lectin receptor (CLR) DC-SIGN was responsible for the trans-infection function of the virus, subsequent studies demonstrated that trans-infection of CD4+ T cells with HIV-1 can also occur through DC-SIGN–independent mechanisms. We demonstrate that a cell surface molecule designated DCIR (for DCimmunoreceptor), a member of a recently described family of DC-expressing CLRs, can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4+ T cells from human immature monocyte-derived DCs. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Data from transfection experiments indicated that DCIR acts as a ligand for HIV-1 and is involved in events leading to productive virus infection. Finally, we show that the neck domain of DCIR is important for the DCIR-mediated effect on virus binding and infection. These results point to a possible role for DCIR in HIV-1 pathogenesis by supporting the productive infection of DCs and promoting virus propagation.
The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in ...regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a "roadblock" to synthesis of the noncoding LncRNA and pRNA that we show are generated from the "Spacer Promoter" duplications present upstream of the 47S pre-rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre-rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells.
Since the introduction of the combined antiretroviral therapy, HIV‐1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general ...population. Nevertheless, various age‐related pathologies such as neurocognitive disorders have emerged as serious complications. A “shock and kill” strategy using latency‐reversing agents (LRA) to reactivate HIV‐1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV‐1‐infected brains, we investigated the consequences of HIV‐1 infection and treatment with two LRA (bryostatin‐1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV‐1‐infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin‐1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ‐loaded microvesicles. Thus, both HIV‐1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV‐1‐infected persons.
Main Points
Infection by HIV‐1 and treatment by latency reversing agents Bryostatin‐1 and JQ1 modify beta‐amyloid uptake and degradation by astrocytes.
JQ1 induced the release of amyloid loaded microvesicles.
Abstract
Communication between gut microbiota and the brain is an enigma. Alterations in the gut microbial community affects enteric metabolite levels, such as short chain fatty acids (SCFAs). SCFAs ...have been proposed as a possible mechanism through which the gut microbiome modulate brain health and function. This study analyzed for the first time the effects of SCFAs at levels reported in human systemic circulation on SH-SY5Y human neuronal cell energy metabolism, viability, survival, and the brain lipidome. Cell and rat brain lipidomics was done using high resolution mass spectrometry (HRMS). Neuronal cells viability, survival and energy metabolism were analyzed via flow cytometer, immunofluorescence, and SeahorseXF platform. Lipidomics analysis demonstrated that SCFAs significantly remodeled the brain lipidome in vivo and in vitro. The most notable remodulation was observed in the metabolism of phosphatidylethanolamine plasmalogens, and mitochondrial lipids carnitine and cardiolipin. Increased mitochondrial mass, fragmentation, and hyperfusion occurred concomitant with the altered mitochondrial lipid metabolism resulting in decreased neuronal cell respiration, adenosine triphosphate (ATP) production, and increased cell death. This suggests SCFAs at levels observed in human systemic circulation can adversely alter the brain lipidome and neuronal cell function potentially negatively impacting brain health outcomes.
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