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71.
Joey Lai Oliver K. Bernhard Stuart G. Turville Andrew N. Harman John Wilkinson Anthony L. Cunningham 《The Journal of biological chemistry》2009,284(17):11027-11038
C-type lectin receptors expressed on the surface of dendritic cells and
macrophages are able to bind glycoproteins of microbial pathogens via mannose,
fucose, and N-acetylglucosamine. Langerin on Langerhans cells,
dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin
on dendritic cells, and mannose receptor (MR) on dendritic cells and
macrophages bind the human immunodeficiency virus (HIV) envelope protein gp120
principally via high mannose oligosaccharides. These C-type lectin receptors
can also oligomerize to facilitate enhanced ligand binding. This study
examined the effect of oligomerization of MR on its ability to bind to mannan,
monomeric gp120, native trimeric gp140, and HIV type 1 BaL. Mass spectrometry
analysis of cross-linked MR showed homodimerization on the surface of primary
monocyte-derived dendritic cells and macrophages. Both monomeric and dimeric
MR were precipitated by mannan, but only the dimeric form was
co-immunoprecipitated by gp120. These results were confirmed independently by
flow cytometry analysis of soluble monomeric and trimeric HIV envelope and a
cellular HIV virion capture assay. As expected, mannan bound to the
carbohydrate recognition domains of MR dimers mostly in a calcium-dependent
fashion. Unexpectedly, gp120-mediated binding of HIV to dimers on
MR-transfected Rat-6 cells and macrophages was not calcium-dependent, was only
partially blocked by mannan, and was also partially inhibited by
N-acetylgalactosamine 4-sulfate. Thus gp120-mediated HIV binding
occurs via the calcium-dependent, non-calcium-dependent carbohydrate
recognition domains and the cysteine-rich domain at the C terminus of MR
dimers, presenting a much broader target for potential inhibitors of gp120-MR
binding.The mannose receptor
(MR)2 is a C-type
lectin receptor that is expressed on the surface of a variety of cells,
including immature monocyte-derived dendritic cells (MDDC), dermal dendritic
cells, macrophages, and hepatic endothelial cells. It is a multifunctional
protein, involved in antigen recognition and internalization during the early
stages of the innate immune response
(1) as well as physiological
clearance of the endogenous pituitary hormones lutropin and thyrotropin
(2,
3). Recognition of foreign
antigens occurs via mannose, fucose, and GlcNAc residues
(4,
5), which are generally not
found as terminal residues on mammalian glycoproteins but are highly abundant
on surface proteins of pathogens such as the HIV-1 envelope gp120
(6,
7). Once bound, pathogens can
be internalized by endocytosis or phagocytosis, where they are targeted to
lysosomes for proteolytic degradation and presentation on major
histocompatibility complex class II
(8). In immature DCs, soluble
recombinant HIV envelope proteins are processed by this pathway, initially
binding to both dendritic cell-specific intracellular adhesion molecule 3
grabbing non-integrin (DC-SIGN) and MR and ultimately co-localizing with MR
but not DC-SIGN in lysosomes
(9). Furthermore, in immature
DCs and to a greater extent mature DCs, a proportion of intact HIV-1 enters a
unique vesicular compartment that co-localizes with tetraspanin proteins such
as CD81 (10,
11). Recently, this
compartment has been shown to be continuous with the plasma membrane
(11) and does not represent a
continuation of the endolysosomal network. Interestingly, this compartment can
translocate virus from DCs to CD4 T cells, upon the formation of a virological
synapse
(10–12).
Although viral uptake can occur in DCs independent of HIV env
(2), the efficiency of HIV
binding and uptake is greatly enhanced by the presence of C-type lectin-env
interactions. At least initial binding to DC-SIGN (and most likely also MR) is
required for T cell trans-infection
(13).Structurally, the extracellular domain of MR consists of an N-terminal
cysteine-rich domain (Cys-RD), followed by a fibronectin type II domain and
eight carbohydrate recognition domains (CRD) on a single polypeptide backbone
(1). Of the eight CRDs, CRD
4–8 have been shown to be required for high affinity binding of ligands
containing terminal mannose/fucose/GlcNAc residues, with CRD 4 having
demonstrable monosaccharide binding in isolation
(14). Binding and release of
ligand within the low pH environment of the endolysosomal compartment are also
Ca2+-dependent. Acid-induced removal of Ca2+ binding in
CRD 4 and 5 was shown to cause a conformational rearrangement of the domain,
resulting in a loss of carbohydrate binding activity
(15). In contrast, binding of
sulfated carbohydrates to the Cys-RD appears to be Ca2+-independent
as no Ca2+-binding sites were observed in its crystal structure
(2,
16).Oligomerization of CLRs such as DC-SIGN
(17), Langerin
(18), and mannose-binding
protein (19) has been reported
to be essential for binding of oligosaccharide-bearing ligands. Early studies
on MR suggested that it exists solely as a monomeric molecule and that
clustering of multiple CRDs within the single polypeptide backbone was
necessary for high affinity binding of oligosaccharide moieties
(20). However, more recent
studies have shown that dimerization is possible in the presence of
Ca2+ (21) and that
an equilibrium may exist between monomeric and dimeric forms on the cell
surface (22). It is currently
unclear what effect dimerization has on ligand binding to the CRDs; however,
there is evidence that dimerization of MR is required for high affinity
binding of ligands bearing terminal N-acetylgalactosamine 4-sulfate
(GalNAc-4-SO4) such as lutropin and thyrotropin
(22) to the Cys-RD.To date, studies on the oligomerization and ligand binding activity of MR
have used solubilized protein from cell lysates
(20) or purified recombinant
fragments (21). Because the
membrane microenvironment can influence protein associations, soluble forms of
MR may not necessarily be a true model of the quaternary structure and
function of the native protein. Here, we used a well established method of
cross-linking (23) on MDDCs,
monocyte-derived macrophages (MDMs), and MR-transfected Rat-6 cells to
preserve lateral protein-protein interactions between MR on the cell surface
prior to solubilization. Mass spectrometry analysis of affinity-purified
complexes showed they were homo-oligomers, and further resolution of the
complex on a low percentage polyacrylamide gel by SDS-PAGE strongly indicates
that they are dimers. Dimerization of MR was also found to be essential for
binding mannan, monomeric gp120, native trimeric gp140, and HIV-1 viral
particles. Persistence of monomeric gp120 and trimeric gp140 binding to
dimeric MR in the presence of EGTA and various CRD and other inhibitors,
however, suggested that gp120-mediated HIV-1 binding is not
Ca2+-dependent and that at least binding probably occurs to both
Ca2+-dependent and -independent CRDs and also the Cys-RD. 相似文献
72.
LINDA FUSELIER PAUL G. DAVISON MARIAH CLEMENTS BLANKA SHAW NICOLAS DEVOS JOCHEN HEINRICHS J
RN HENTSCHEL MARKO SABOVLJEVIC PTER SZ
VNYI SCOTT SCHUETTE WOLFGANG HOFBAUER A. JONATHAN SHAW 《Biological journal of the Linnean Society. Linnean Society of London》2009,98(4):745-756
Seed plant genera often exhibit intercontinental disjunctions where different species are found on different continents. Many morphologically circumscribed bryophyte species exhibit similar disjunctions. We used nucleotide sequences from the plastid and nuclear genomes to test hypotheses of phylogeography within representatives of the genus Metzgeria: Metzgeria furcata, Metzgeria conjugata, and Metzgeria myriopoda. The first two species have sexual and asexual populations, exhibit disjunctions between North America and Europe, and have been split into separate species, numerous subspecies or varieties. The third species occurs in eastern North America but is not reported from Europe. Phylogenetic analyses resolved three distinct lineages within the morphologically defined species, M. furcata: one in North America, and two in Europe. Similarly, three morphologically cryptic clades of M. conjugata were resolved by the molecular data: northern North America, Europe, and south‐eastern North America. For both species, molecular divergence among taxa occurred in the absence of morphological change. In the case of M. myriopoda, all plants from eastern North America were both morphologically uniform and genetically homogeneous (although not identical). The present study provides significant insight into a plant group with complex taxonomy, and indicates that these liverwort taxa with wide distributions, extreme sex ratios, and continental disjunctions harbor cryptic lineages. © 2009 The Linnean Society of London, Biological Journal of the Linnean Society, 2009, 98 , 745–756. 相似文献
73.
Xing GUO Mark P. SIMMONS Paul Pui‐Hay BUT Pang‐Chui SHAW Rui‐Jiang WANG 《植物分类学报:英文版》2011,49(3):203-212
The potential application of DNA barcodes of plastid (matK, trnH–psbA, petD, and rbcL) and nuclear (internal transcribed spacer (ITS) of rDNA) DNA regions was investigated for 25 Hedyotis taxa. The ITS showed the best species discrimination by resolving 23 of the species as exclusive lineages with no shared alleles between any of the 24 distinct species (H. assimilis and H. mellii are not supported as distinct species based on our molecular and morphological data). Conversely, rbcL performed the worst and only resolved 10 of the species as exclusive lineages, and 10 species with shared alleles. Using ITS has the advantage of high PCR amplification success and it provides good intra- and interspecific variation distribution patterns. The most powerful plastid markers were petD and trnH–psbA, but we could amplify and sequence trnH–psbA for only 83% of the accessions sampled. Combination of ITS and petD performed extremely well, with all 24 of the distinct species resolved as exclusive lineages and no shared alleles between any of the distinct species. We therefore recommend ITS, or a combination of ITS and petD, as the standard DNA barcode in Hedyotis, but acknowledge that there are no shared alleles between distinct species for matK and rbcL combined. 相似文献
74.
George EM Arany M Cockrell K Storm MV Stec DE Granger JP 《American journal of physiology. Regulatory, integrative and comparative physiology》2011,301(5):R1495-R1500
Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5-10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14-19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ~17% in response to sFlt-1 infusion but was increased ~50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE. 相似文献
75.
Preeclampsia is a serious and common hypertensive complication of pregnancy, affecting ~5 to 8 % of pregnancies. The underlying cause of preeclampsia is believed to be placental ischemia, which causes secretion of pathogenic factors into the maternal circulation. While a number of these factors have been identified, it is likely that others remain to be elucidated. Here, we have utilized a relevant preclinical rodent model of placental ischemia-induced hypertension, the reduced uterine perfusion pressure (RUPP) model, to determine the effect of chronic placental ischemia on the underlying chorionic tissue and placental villi. Tissue from control and RUPP rats were isolated on gestational day 19 and mRNA from these tissues was subjected to microarray analysis to determine differential gene expression. At a statistical cutoff of p < 0.05, some 2,557 genes were differentially regulated between the two groups. Interestingly, only a small subset (22) of these genes exhibited changes of greater than 50 % versus control, a large proportion of which were subsequently confirmed using qRT-PCR analysis. Network analysis indicated a strong effect on inflammatory pathways, including those involving NF-κB and inflammatory cytokines. Of the most differentially expressed genes, the predominant gene classes were extracellular remodeling proteins, pro-inflammatory proteins, and a coordinated upregulation of the prolactin genes. The functional implications of these novel factors are discussed. 相似文献
76.
Ammonium ions at a concentration of 1 mM completely inhibitthe growth and further development of 1215 hr germlingsof Schizophyllum commune. The NH4+, inhibition of germling growthis reversed by acetate and pyruvate, but it is reversed moreeffectively by TCA intermediates. Glucose, is not effectivein reversing the ammonium inhibition. From these data it isapparent that functional TCA enzymes are present in the germlingstage and that the mechanisms for incorporating acetate andpyruvate into the TCA cycle are also operative. There may be,however, an impaired glycolytic pathway, and, as a consequence,no intermediates are supplied to the TCA cycle, making the germlingssensitive to a disruption in the TCA cycle. The possible modeof action of ammonium ions is the activation of NADP-glutamatedehydrogenase, the subsequent enhancement of glutamic acid biosynthesis,and the final depletion of TCA intermediates.
1This investigation was supported in part by Research GrantAI-06570 from the National Institute of Allergy and InfectiousDiseases of the U.S. Public Health Service (Received January 26, 1970; ) 相似文献
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