Gram-Negative Bacterial Endotoxin LPS Induces NeuGc Loss through Ets1-Dependent Downregulation of Intestine-Specific pcmah Transcript in Porcine Intestinal Cells.

Choong-Hwan Kwak,Kwon-Ho Song,Cheorl-Ho Kim

doi:10.3390/ijms21144892

Abstract

N-glycolylneuraminic acid (NeuGc), a non-human sialic acid derivative synthesized by cytidine-5′-monophospho-N-acetylneuraminic acid hydroxylase (CMAH), plays a crucial role in mediating infections by certain pathogens. Although it has been postulated that NeuGc biosynthesis and CMAH expression are downregulated during microbial infection, the underlying mechanisms remain unclear. The present study showed that exposure to lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, leads to loss of NeuGc biosynthesis in pig small intestinal I2I-2I cells. This LPS-induced NeuGc loss was accompanied by decreased CMAH transcript levels, especially intestine-specific 5′pcmah-1. Furthermore, LPS suppressed the activity of the Pi promoter responsible for 5′pcmah-1 by inhibiting DNA binding of Est1. These findings provide insight into the regulatory mechanisms of Neu5Gc biosynthesis during pathogenic infectious events, which may represent a host defense mechanism that protects the self against pathogenic bacterial infections even in non-sanitary environments.

Highlights

Sialic acids are typically found at the non-reducing ends of oligosaccharide chains, which are involved in various biological processes, such as the immune response and infections [1,2]
To investigate the effects of bacterial endotoxin on NeuGc biosynthesis, pig small intestinal IPI-2I cells were treated with 100 ng/mL LPS
LPS treatment resulted in a time-dependent gradual loss of cytidine-5 -monophospho-N-acetylneuraminic acid hydroxylase (CMAH) protein, which was accompanied by decreased levels of CMAH mRNA (Figure 1b,c)

Summary

Introduction

Sialic acids are typically found at the non-reducing ends of oligosaccharide chains, which are involved in various biological processes, such as the immune response and infections [1,2]. N-glycolylneuraminic acid (NeuGc) is one of the major types of sialic acid found in most mammals except in humans in physiological state [3]. NeuGc-containing glycoconjugates have been implicated as a crucial mediator in the infection process [4,5,6,7,8]. Accumulating evidence indicates that the NeuGc level is regulated during the developmental process as well as upon infection by intestinal parasites [4,5,9]. The NeuGc level is downregulated by the rat intestinal parasite Nippostrongylus brasiliensis [5]. These findings raise the obvious question of precisely how NeuGc levels are regulated in the course of infection

Methods

Results

Discussion

Conclusion