Evolution and comparative analysis of the MHC Class III inflammatory region

Deakin, Janine E.; Papenfuss, Anthony T.; Belov, Katherine; Cross, Joseph G. R; Coggill, Penny; Palmer, Sophie; Sims, Sarah; Speed, Terence P.; Beck, Stephan; Graves, Jennifer A. Marshall

doi:10.1186/1471-2164-7-281

Cited by 63 publications

(45 citation statements)

References 58 publications

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“…The latter observation is explained by the lipocalin structure of apoM where a small hydrophobic binding pocket enables binding of small lipophilic molecules (14). It is interesting to note that apoM is also found in a highly conserved major histocompatibility complex class III cluster in primitive organisms such as fish, indicating conservation of the cluster for more than 450 million years (37), further suggesting that apoM may have essential biological functions. The present data document that the signal peptide in apoM serves an important function by anchoring the apolipoprotein to lipoproteins, thus inhibiting the elimination of apoM in the kidney and maintaining stable apoM concentrations in plasma.…”

Section: Discussionmentioning

confidence: 93%

The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma

Christoffersen

Ahnström

Axler

et al. 2008

Journal of Biological Chemistry

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Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic ␣-helixes and ␤-sheets. Plasma apolipoprotein (apo) M lacks an external amphipathic motif but, nevertheless, is exclusively associated with lipoproteins (mainly high density lipoprotein). Uniquely, however, apoM is secreted to plasma without cleavage of its hydrophobic NH 2 -terminal signal peptide. To test whether the signal peptide serves as a lipoprotein anchor for apoM in plasma, we generated mice expressing a mutated apoM Q22A cDNA in the liver (apoM Q22A -Tg mice (transgenic mice)) and compared them with mice expressing wild-type human apoM (apoM-Tg mice). The substitution of the amino acid glutamine 22 with alanine in apoM Q22A results in secretion of human apoM without a signal peptide. The human apoM mRNA level in liver and the amount of human apoM protein secretion from hepatocytes were similar in apoM-Tg and apoM Q22A -Tg mice. Nevertheless, human apoM was not detectable in plasma of apoM Q22A -Tg mice, whereas it was easily measured in the apoM-Tg mice. To examine the plasma metabolism, recombinant apoM lacking the signal peptide was produced in Escherichia coli and injected into wild-type mice. The apoM without signal peptide did not associate with lipoproteins and was rapidly cleared in the kidney. Accordingly, ligation of the kidney arteries in apoM Q22A -Tg mice resulted in rapid accumulation of human apoM in plasma. The data suggest that hydrophobic signal peptide sequences, if preserved upon secretion, can anchor plasma proteins in lipoproteins. In the case of apoM, this mechanism prevents rapid loss by filtration in the kidney.Lipoproteins consist of lipids (mainly cholesterol, phospholipids, and triglycerides) solubilized by apolipoproteins. The apolipoproteins play essential roles in controlling plasma and tissue lipid homeostasis by interacting with cellular lipoprotein receptors (the low density lipoprotein receptor, the scavenger receptor class B type-I, the ATP-binding cassette transporter AI, etc.) and enzymes (e.g. lecithin-cholesterol acyltransferase, hepatic lipase, and lipoprotein lipase) and lipid transfer protein (cholesteryl ester transfer protein and phospholipid transfer protein). However, several apolipoproteins have roles beyond lipid metabolism. Indeed, a recent shotgun proteomic approach revealed that HDL 3 on average contains Ͼ40 proteins, of which many affect complement activation or protease inhibition (1). Also, several well known HDL apolipoproteins have roles in inflammation and host defense against microbial infections (1). For instance, apoL is involved in fighting Trypanosoma infections (2), and apoJ (clusterin) has even been proposed to play a significant role in tumorigenesis (3). For apolipoproteins without any (known) effect on plasma lipid metabolism, it is conceivable that the host HDL particle mainly serves as a carrier that prevents rapid removal of its associated apolipoproteins (e.g. by filtration in the kidney) or perh...

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Section: Discussionmentioning

confidence: 93%

The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma

Christoffersen

Ahnström

Axler

et al. 2008

Journal of Biological Chemistry

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“…3b). Notably, the arrangement and orientation of the three genes has been preserved in mammalian evolution and is conserved between placentals and marsupials [31, 213]. It remains to be determined whether the TNF gene moves into an area where RNA polymerase II and actively transcribing genes are colocalized, that is, a bona fide transcription factory [202, 203], although it is interesting to note that both LPS stimulation and monocyte differentiation drives the TNF locus from heterochromatin to euchromatin, which correlates with the cells’ ability to produce TNF [186].…”

Section: Higher-order Intrachromosomal Interactions At the Tnf/lymphomentioning

confidence: 99%

Transcriptional Control of the TNF Gene

Falvo¹,

Tsytsykova²,

Goldfeld³

2010

Current Directions in Autoimmunity

220

170

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The cytokine TNF is a critical mediator of immune and inflammatory responses. The TNF gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving the recruitment of distinct sets of transcription factors to a compact and modular promoter region. In this review, we describe our current understanding of the mechanisms through which TNF transcription is specifically activated by a variety of extracellular stimuli in multiple cell types, including T cells, B cells, macrophages, mast cells, dendritic cells, and fibroblasts. We discuss the role of nuclear factor of activated T cells and other transcription factors and coactivators in enhanceosome formation, as well as the contradictory evidence for a role for nuclear factor κB as a classical activator of the TNF gene. We describe the impact of evolutionarily conserved cis-regulatory DNA motifs in the TNF locus upon TNF gene transcription, in contrast to the neutral effect of single nucleotide polymorphisms. We also assess the regulatory role of chromatin organization, epigenetic modifications, and long-range chromosomal interactions at the TNF locus.

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“…fish and frogs) (21). In humans and mice, apoM is expressed in hepatocytes and in kidney proximal tubule cells (2,22).…”

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confidence: 99%

Effect of Apolipoprotein M on High Density Lipoprotein Metabolism and Atherosclerosis in Low Density Lipoprotein Receptor Knock-out Mice

Christoffersen

Jauhiainen

Moser

et al. 2008

Journal of Biological Chemistry

171

179

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To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM ؊/؊ ) mice. Plasma apoM was predominantly associated with 10 -12-nm ␣-migrating HDL particles. Human apoM overexpression (11-fold) increased plasma cholesterol concentration by 13-22%, whereas apoM deficiency decreased it by 17-21%. The size and charge of apoA-I-containing HDL in plasma were not changed in apoM-Tg or apoM ؊/؊ mice. However, in plasma incubated at 37°C, lecithin:cholesterol acyltransferase-dependent conversion of ␣-to pre-␣-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre-␤-migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 ؎ 1.1%, p ‫؍‬ 0.06) and decreased in apoM ؊/؊ mice (0.5 ؎ 0.3%, p ‫؍‬ 0.03) versus controls (1.8 ؎ 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with ϳ2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic modulation of plasma HDL particles, increased cholesterol efflux from foam cells, and an antioxidative effect of apoM-containing HDL.Epidemiological studies have demonstrated a strong inverse association between plasma HDL 3 concentrations and risk of premature coronary heart disease (1). However, the molecular heterogeneity of HDL has posed difficulties in understanding HDL metabolism and its effects in atherogenesis. In 1999, Xu and Dahlbäck (2) discovered apoM, which is mainly associated with HDL, with smaller amounts in LDL and VLDL. ApoM appears to have a novel role in murine HDL metabolism by affecting pre-␤-HDL formation (3). Pre-␤-HDL is considered antiatherogenic, because it mediates ATP-binding cassette transporter A1 (ABCA1)-dependent efflux of cholesterol from foam cells as part of the reverse cholesterol transport. Pre-␤-HDLs, the precursor of mature HDLs, are ϳ7-nm particles containing apoA-I and phospholipid and can be derived from two sources (4, 5). First, pre-␤-HDL can arise from newly synthesized hepatic apoA-I, acquiring free cholesterol and phospholipids through the interaction of apoA-I with ABCA1 (6). The small phospholipid-containing apoA-I particles can act via ABCG1 and remove cholesterol from foam cells (7-9). The free cholesterol in HDL can be esterified by lecithin:cholesterol acyltransferase (LCAT) (10, 11), changing the electrophoretic mobility of HDL from pre-␤ to ␣ (12-14). In mice, overexpression of LCAT converts ␣-HDL to pre-␣-HDL (15). Second, pre-␤-HDL can arise from ␣-HDL through the action of phospholipid transfer protein (PLTP), which induces fusion of ␣-HDL particles and concomitant dissociation of small pre-␤-HDL particles (16 -18). Also, hepatic lipase (HL) can generate pre-␤-HDL from ␣-HDL through its triglyceride lipase activity, either in concert with cholesteryl ester transfer protein (19) or alone (as in mice, w...

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Evolution and comparative analysis of the MHC Class III inflammatory region

Cited by 63 publications

References 58 publications

The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma

The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma

Transcriptional Control of the TNF Gene

Effect of Apolipoprotein M on High Density Lipoprotein Metabolism and Atherosclerosis in Low Density Lipoprotein Receptor Knock-out Mice

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