Humoral immunity against the proline-rich peptide epitope of the IgA1 hinge region in IgA nephropathy

Kokubo, Tohru; Hashizume, Katsuhito; Iwase, Hitoo; Arai, Kenji; Tanaka, Atsushi; Toma, Kazunori; Hotta, Kyoko; Kobayashi, Yutaka

doi:10.1093/ndt/15.1.28

Cited by 36 publications

(29 citation statements)

References 26 publications

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“…1(a), the region from aa 316 to 378 is a functionally uncharacterized domain between the processivity and nuclear-localization domains of BMRF1. This region encompasses a proline-and serine/threonine-rich domain that is very similar to the hinge regions identified in human IgA and other proteins (Kerr, 1990;Kokubo et al, 2000;Zhou et al, 1995). Hinge regions of these proteins are phosphorylated at their CDK target sites and are crucial for inducing conformational changes of these proteins (Knotts et al, 2001;Zhou et al, 1995).…”

Section: Bglf4 Target Residues Are Located Within Aa 316-378 Of Bmrf1mentioning

confidence: 98%

Effect of phosphorylation on the transactivation activity of Epstein–Barr virus BMRF1, a major target of the viral BGLF4 kinase

Yang

Chang

Tsai

et al. 2008

Journal of General Virology

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Modification of human herpesvirus DNA polymerase processivity factors (PFs) by phosphorylation occurs frequently during viral lytic replication. However, functional regulation of the herpesvirus PFs through phosphorylation is not well understood. In addition to processivity, the PF BMRF1 of Epstein-Barr virus can function as a transactivator to activate the BHLF1 promoter within the lytic origin of replication (oriLyt), which is assumed to facilitate DNA replication through remodelling viral chromatin structure. BMRF1 is known to be phosphorylated by the viral BGLF4 kinase, but its impact on BMRF1 function is unclear. Seven candidate BGLF4 target sites were predicted within a proline-rich region between the DNA-processivity and nuclear-localization domains of BMRF1. We show that four of these residues, Ser-337, Thr-344, Ser-349 and Thr-355, are responsible for the BGLF4-induced hyperphosphorylation of BMRF1. In functional analyses, a phosphorylation-mimicking mutant of BMRF1 shows similar nuclear localization, as well as DNA-binding ability, to the wild type; however, it displays stronger synergistic activation of the BHLF1 promoter with Zta. Notably, BGLF4 downregulates BMRF1 transactivation and enhances the transactivation activity of Zta and the synergistic activation of BMRF1 and Zta on the BHLF1 promoter. Our findings suggest that BGLF4 may modulate the activation of the oriLyt BHLF1 promoter coordinately through multiple mechanisms to facilitate optimal oriLyt-dependent viral DNA replication. INTRODUCTIONEpstein-Barr virus (EBV) is a gamma-1 human herpesvirus that infects most of the human population worldwide. EBV infection is associated closely with several human malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin's disease (Cohen, 2000;Young & Rickinson, 2004). Even though the virus is present in a latent form in most cancer tissues, elevated serum antibody titres against some EBV lytic antigens have been used as diagnostic markers for NPC (Chien et al., 2001) and the serum viral DNA load is an important prognostic parameter for NPC patients (Lin et al., 2004). Thus, the progression of lytic replication is important for the pathogenesis of EBV-associated malignancy.Transcription-coupled viral DNA replication is a common phenomenon among human herpesviruses for the initiation of lytic replication. The promoters within lytic origin of replication (oriLyt) regions, which have been identified in human cytomegalovirus, Kaposi's sarcoma-associated virus (KSHV or human herpesvirus 8) and EBV, are crucial for viral lytic replication (AuCoin et al., 2004;Hammerschmidt & Sugden, 1988;Xu et al., 2004). Because the promoter regions within oriLyt are important for viral replication and can be substituted by other functional promoters, the transcription machinery has been suggested to remodel the viral chromatin structure and thereby facilitate the binding of the DNA polymerase complex to the viral DNA template (Xu et al., 2004).In addition to DNA polymerase, functional replic...

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Section: Bglf4 Target Residues Are Located Within Aa 316-378 Of Bmrf1mentioning

confidence: 98%

Effect of phosphorylation on the transactivation activity of Epstein–Barr virus BMRF1, a major target of the viral BGLF4 kinase

Yang

Chang

Tsai

et al. 2008

Journal of General Virology

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“…It was demonstrated in IgAN patients that the O-glycosylation pattern of the IgA1 hinge region was abnormal, with reduced galactose and/or sialic acid content, leading to increased exposure of the internal GalNAc [Allen, 1995;Coppo and Amore, 2004;Hiki et al, 1998], which could form a new antigen. This aberrant glycosylation of serum IgA1 could favor self-aggregation and formation of macromolecular complexes including the anti-IgA1 hinge peptide antibody [Coppo and Amore, 2004;Iwase et al, 1999;Kokubo et al, 2000]. Abnormally glycosylated IgA1 may also escape clearance by hepatic receptors for asialoglycoproteins [Basset et al, 1999].…”

Section: Introductionmentioning

confidence: 99%

Variants of theST6GALNAC2promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy

Zhu

Zhang

et al. 2007

Hum. Mutat.

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IgA nephropathy (IgAN) is a polygenic disorder. Increasing evidence has implicated that aberrant glycosylation of IgA1 molecules, including alpha2,6 sialic acid defects, are involved in the pathogenesis of IgAN. In the present study, we designed an association study to investigate polymorphisms of two important genes, ST6GALNAC2 and NEU1, which are involved in the sialylation of the IgA1 molecule, in the susceptibility to IgAN. A total of 670 patients with histologically proven IgAN and 494 healthy controls were enrolled. Screening of SNPs in the coding and promoter regions of the ST6GALNAC2 and NEU1 genes was performed by sequencing. ST6-SNP1 (c.-988A>G), ST6-SNP2 [rs3840858:D>I(CGGC), c.-450_-449insCGGC], ST6-SNP3 (rs1867561:C>G, c.-135C>G), and ST6-SNP7 (rs2304921:G>A, c.186+12G>A) in the ST6GALNAC2 gene were selected as tagging SNPs. Functional evaluations of targets were assayed by luciferase activity. The alpha2,6 sialic acid contents of serum IgA1 in 497 patients were analyzed. Our results demonstrated that the frequency of haplotype ADG in the promoter region of ST6GALNAC2 was significantly higher in IgAN patients than that in controls (p=0.0069; odds ratio [OR]=1.36; 95% confidence interval [CI], 1.08-1.72). Furthermore, the ADG haplotype was associated with the deficient degrees of alpha2,6 sialic acid of IgA1 molecules in IgAN patients (r=0.408, p=0.0035). The ADG haplotype conferred significantly reduced promoter activity compared with the most common haplotype GDG in vitro (196.43+/-21.55 vs. 258.41+/-46.25; p=0.002). In the present study, we identified for the first time the ADG haplotype in the ST6GALNAC2 gene as a functional regulatory variant that may contribute to the genetic susceptibility in a subset of patients in whom the desialylation of IgA1 molecules was the main causative pathogenesis of IgAN.

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“…In the absence of Gal, the terminal sugar is GalNAc (19,20). Subsequently, these aberrant O-glycans or HR glycopeptides (23,24) are recognized by naturally occurring antibodies with anti-glycan or anti-HR peptide specificities (20,24), and thus circulating immune complexes are formed (25). It is hypothesized that these Gal-deficient IgA1-containing circulating immune complexes are not efficiently cleared in IgAN patients and thus deposit in the mesangium where they bind to and activate the resident mesangial cells, inducing cellular proliferation and matrix overproduction (9,26).…”

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confidence: 99%

Determination of Aberrant O-Glycosylation in the IgA1 Hinge Region by Electron Capture Dissociation Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry

Renfrow

Cooper

Tomana

et al. 2005

Journal of Biological Chemistry

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Humoral immunity against the proline-rich peptide epitope of the IgA1 hinge region in IgA nephropathy

Abstract: These results suggested that the peptide epitope of the IgA1 hinge region which was aberrantly exposed by underglycosylation could induce the humoral immune response in IgAN.

Cited by 36 publications

References 26 publications

Effect of phosphorylation on the transactivation activity of Epstein–Barr virus BMRF1, a major target of the viral BGLF4 kinase

Effect of phosphorylation on the transactivation activity of Epstein–Barr virus BMRF1, a major target of the viral BGLF4 kinase

Variants of theST6GALNAC2promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy

Determination of Aberrant O-Glycosylation in the IgA1 Hinge Region by Electron Capture Dissociation Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry

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