Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum

Vanhollebeke, Benoît; Nielsen, Marianne Jensby; Watanabe, Yoshihisa; Truc, Philippe; Vanhamme, Luc; Nakajima, Kazunori; Moestrup, Søren K.; Pays, Étienne

doi:10.1073/pnas.0609902104

Cited by 64 publications

(68 citation statements)

References 33 publications

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“…So far, only human ApoL1 and ApoL6 have been characterized. ApoL1 is a secreted protein protective against trypanosomiasis (45). Other members of the ApoL family are predicted to lack a signal peptide, and it is unclear whether they are secreted.…”

Section: Discussionmentioning

confidence: 99%

Inefficient Type I Interferon-Mediated Antiviral Protection of Primary Mouse Neurons Is Associated with the Lack of Apolipoprotein L9 Expression

Kreit

Stolzmann

Knoops

et al. 2014

J Virol

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We examined the antiviral response promoted by type I interferons (IFN) in primary mouse neurons. IFN treatment of neuron cultures strongly upregulated the transcription of IFN-stimulated genes but conferred a surprisingly low resistance to infection by neurotropic viruses such as Theiler's murine encephalomyelitis virus (TMEV) or vesicular stomatitis virus (VSV). Response of primary mouse neurons to IFN treatment was heterogeneous, as many neurons failed to express the typical IFN response marker Mx1 after IFN treatment. This heterogeneous response of primary neurons correlated with a low level of basal expression of IFN-stimulated genes, such as Stat1, that are involved in signal transduction of the IFN response. In addition, transcriptomic analysis identified 15 IFN-responsive genes whose expression was low in IFN-treated primary neurons compared to that of primary fibroblasts derived from the same mice (Dhx58, Gvin1, Sp100, Ifi203 isoforms 1 and 2, Irgm2, Lgals3bp, Ifi205, Apol9b, Ifi204, Ifi202b, Tor3a, Slfn2, Ifi35, Lgals9). Among these genes, the gene coding for apolipoprotein L9b (Apol9b) displayed antiviral activity against Theiler's virus when overexpressed in L929 cells or in primary neurons. Accordingly, knocking down Apol9b expression in L929 cells increased viral replication. Therefore, we identified a new antiviral protein induced by interferon, ApoL9b, whose lack of expression in primary neurons likely contributes to the high sensitivity of these cells to viral infection. IMPORTANCE The type I interferon (IFN) response is an innate immune defense mechanism that is critical to contain viral infection in the hostuntil an adaptive immune response can be mounted. Neurons are a paradigm for postmitotic, highly differentiated cells. Our data show that primary mouse neurons that are exposed to type I interferon remain surprisingly susceptible to viral infection. On one hand, the low level of basal expression of some factors in neurons might prevent a rapid response of these cells. On the other hand, some genes that are typically activated by type I interferon in other cell types are expressed at much lower levels in neurons. Among these genes is the gene encoding apolipoprotein L9, a protein that proved to have antiviral activity against the neurotropic Theiler's murine encephalomyelitis virus. Our data suggest important functional differences in the IFN response mounted by specific cell populations.

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Section: Discussionmentioning

confidence: 99%

Inefficient Type I Interferon-Mediated Antiviral Protection of Primary Mouse Neurons Is Associated with the Lack of Apolipoprotein L9 Expression

Kreit

Stolzmann

Knoops

et al. 2014

J Virol

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“…In plasma, all three proteins are mainly in the HDL fraction. The apoM-containing HDL fraction is not enriched in PON-1 and HRP (9), and HRP is mainly part of an HDL subfraction named the trypanosome lytic complex, which also contains apoA-I and apoL (17,31). Thus, the signal peptides do not anchor the three proteins to the same HDL subfraction.…”

Section: Discussionmentioning

confidence: 99%

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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“…According to this documented model, apoL-I accounts for the actual trypanolytic activity by its membrane-disruptive activity, whereas Hpr plays an indirect yet essential role in trypanolysis, by acting as a ligand for a receptor localized on the surface of the parasite. Hpr is thus crucial for efficient uptake of the associated apoL-I 85,91,92 but possesses no direct lytic activity itself, 91 as recently demonstrated in an apoL-I/Hpr transgenic mouse model. 93 Later, Hb came into play when it was somewhat surprisingly demonstrated that Hpr binds Hb with high affinity, 36 thus contradicting previous assumptions of Hpr being inactive in terms of Hb binding.…”

Section: Org Frommentioning

confidence: 98%

“…87,88 Interestingly, the TLF1 has also been reported to combat Leishmania, but the molecular mechanism remains to be defined. 89 The apparent controversies regarding the identity of the lytic factor 90 were finally explained by Vanhollebeke et al, 91 who used human sera lacking either Hpr or apoL-I to demonstrate that Hpr and apoL-I perform separate functions in the trypanolytic mechanism. According to this documented model, apoL-I accounts for the actual trypanolytic activity by its membrane-disruptive activity, whereas Hpr plays an indirect yet essential role in trypanolysis, by acting as a ligand for a receptor localized on the surface of the parasite.…”

Section: Org Frommentioning

confidence: 99%

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Nielsen

Moestrup

2009

Blood

138

109

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Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobinrelated protein, the receptor also takes up the complex of hemoglobin and the HDL- IntroductionHaptoglobin (Hp), an abundant acute phase plasma glycoprotein of the ␣ 2 -globulin fraction, was initially reported in 1938 by Polonovski and Jayle to be a "plasma substance" that binds hemoglobin (Hb). 1 In agreement with this initial characterization and its designation as "haptoglobin" (Greek: haptein, "to bind" ϩ [hemo]globin), Hp has a well-established role in binding of "free" Hb released into the circulation during the process of intravascular hemolysis. By capturing the liberated Hb, Hp protects against toxic effects associated with Hb, and it facilitates Hb clearance through endocytosis by the macrophage scavenger receptor CD163. 2 Later studies of human and primate plasma revealed variant forms of Hp as well as the existence of an Hp-related protein (Hpr) that recently has been shown also to bind Hb. As highlighted in this review, novel functions of Hp depend on high-affinity interactions with Hb and lipoprotein and subsequent receptor recognition of the resulting complexes. Toxicity of hemoglobin released during intracellular hemolysisIntravascular hemolysis, which accounts for approximately 10% to 20% of total red blood cell destruction, 3 changes Hb from being an intracellular O 2 /CO 2 transporter to a highly toxic substance in plasma. This toxicity arises from the heme iron, which can react with endogenous hydrogen peroxide to produce free radicals, which in turn may cause severe oxidative tissue damage, 4 particularly in the kidney. 5 In addition to the oxidative toxicity of Hb, Hb is a potent scavenger of nitric oxide (NO), a signaling molecule that functions as a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression, and platelet activation and aggregation. 6,7 The reaction of Hb with NO is fast and irreversible, leading to the production of nitrate and methemoglobin. If allowed to occur, this Hbmediated consumption of vascular NO, referred to as NOscavenging, thus limits the bioavailabili...

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Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum

Cited by 64 publications

References 33 publications

Inefficient Type I Interferon-Mediated Antiviral Protection of Primary Mouse Neurons Is Associated with the Lack of Apolipoprotein L9 Expression

Inefficient Type I Interferon-Mediated Antiviral Protection of Primary Mouse Neurons Is Associated with the Lack of Apolipoprotein L9 Expression

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

Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

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