Epigenetic reprogramming of UDP‐N‐acetylglucosamine 2‐ epimerase/N‐acetylmannosamine kinase (GNE) in HIV‐1‐ infected CEM T cells

Abstract

Sialylated glycoconjugates mediate several key lymphocyte functions. We previously reported that hyposialylation occurred in latently HIV-1-infected CEM T cells, despite the fully preserved catalytic activity of several sialyltransferases. We show now that these cells are affected by a down-regulation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), which leads to a dramatic decrease in the synthesis of CMP-sialic acid, the donor substrate of all sialyltransferases. The GNE gene promoter was found to be located in a CpG island with several regulatory motifs CREB, SP1, and AP-2. De novo hypermethylation of this promoter was observed in HIV-1-infected CEM cells. This phenomenon might explain some immunological disorders that persist in infected individuals despite long-term therapeutically controlled viral replication. Indeed, an overall decrease in sialic acid engraftment can affect glycoproteins, notably those in which the sialylation status is crucial to ensure homing, recirculation, and survival of lymphocytes.

UDP-GlcNAc 2-Epimerase/ManNAc Kinase (GNE): A Master Regulator of Sialic Acid Synthesis

“…Overall GNE transcription can be regulated by CpG methylation [36] (see also section 7). Interestingly, the CpG islets responsible for this mechanism are localized upstream of exon A1 and not of exon 1 [37]. Although CpG methylation of the GNE gene was unequivocally shown only in lymphocytes, it is very likely, that the same mechanismoccurs in other tissues and contributes to tissue-specific adjustment of GNE expression.…”

“…However, transcription of the GNE gene is unequivocally influenced by an epigenetic event. Methylation of CpG islets in the GNE promoter region leads to down regulation of GNE transcription in several cancer cell lines [36] and in HIV-infected lymphocytes [37]. GNE protein expression and enzyme activity are reduced below detectable levels in these cell lines.…”

“…In HIV-1 infected T lymphocytes, hypomethylation of the GNE promoter was demonstrated to underlie decreased UDP-GlcNAc 2-epimerase enzyme activity and hyposialylation. Interestingly, the changes in this cell line could be entirely corrected by complementation with ManNAc in the growth medium [37]. Regenerating rat hepatocytes were shown to be hyposialylated due to decreased UDP-GlcNAc 2-epimerase enzyme activity.…”

Epigenetic reprogramming of host genes in viral and microbial pathogenesis

“…HIV infection of T lymphocytes in culture also causes promoter methylation of the gene GNE , which encodes a key enzyme in sialic acid biosynthesis, and represses its transcription [60]. This might lead to disruption of cell surface sialylation, which is important in cell–cell recognition and might have important effects on lymphocyte trafficking.…”

Microbe-Induced Epigenetic Alterations

“…HIV infection may disturb, however, these basic functions of T cells by blocking the sialylation of surface glycoproteins involved in these processes. Giordanengo et al ( 2004 ) described that the promoter of the GNE gene became hypermethylated in HIV-infected T cell lines. GNE encodes UDP-N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase that generates the sialyl-donor substrate for cellular sialyltransferases.…”