Ribosome Inactivation Leads to Attenuation of Intestinal Polymeric Ig Receptor Expression via Differential Regulation of Human Antigen R

Abstract

The polymeric IgR (pIgR) is a central component in the transport of IgA across enterocytes and thereby plays a crucial role in the defense against enteropathogens and in the regulation of circulating IgA levels. The present study was performed to address the novel regulation of pIgR expression in intestinal epithelia undergoing ribosome inactivation. Insults to mucosa that led to ribosome inactivation attenuated pIgR expression in enterocytes. However, IFN regulatory factor-1 (IRF-1) as a central transcription factor of pIgR induction was superinduced by ribosome inactivation in the presence of IFN-γ as a result of mRNA stabilization by the RNA-binding protein HuR. Another important transcription factor for pIgR expression, NF-κB, was marginally involved in suppression of pIgR by ribosome inactivation. In contrast to a positive contribution of HuR in early induction of IRF-1 expression, extended exposure to ribosome inactivation caused nuclear entrapment of HuR, resulting in destabilization of late-phase–induced pIgR mRNA. These HuR-linked differential regulations of pIgR and of IRF-1 led to a reduced mucosal secretion of IgA and, paradoxically, an induction of IRF-1–activated target genes, including colitis-associated IL-7. Therefore, these events can account for ribosome inactivation–related mucosal disorders and provide new insight into interventions for HuR-linked pathogenesis in diverse mucosa-associated diseases, including inflammatory bowel disease and IgA nephritis.

Genome-Wide DNA Methylome and Transcriptome Analysis of Porcine Intestinal Epithelial Cells upon Deoxynivalenol Exposure

“…Recent reports mainly focused on the expression of genes involved in these processes and the phenotypic consequences of cell viability and intestinal immunity and functions induced by DON exposure. 36,37 Our data set offers a layer of epigenetic insights for comprehensively deciphering the molecular mechanisms underlying DON toxic effects on the intestinal cells.…”

Dynamic Malignant Wave of Ribosome-Insulted Gut Niche via the Wnt-CTGF/CCN2 Circuit

“…To fully understand this negative circuit between CTGF and Wnt signaling, we sought to identify the nuclear translocation mechanism of b-catenin in our ribosomal insult model. Ribosomal dysfunction triggers the cytosolic translocation of HuR (human antigen R, ELAV-like protein 1) (Do et al, 2013(Do et al, , 2016, which post-transcriptionally regulates target mRNA by directly binding transcripts in AU-rich regions of their 3 0 UTRs, thus enhancing transcript stability (Matoulkova et al, 2012). In our model, co-localization of HuR and CTGF was significantly enhanced in mouse colons with ribosomal insults (Figure 2J).…”

EpCAM Is Essential to Maintaining the Immune Homeostasis of Intestines via Keeping the Expression of pIgR in the Intestinal Epithelium of Mice

“…The interferon-stimulated response element (ISRE) in the exon 1 of PIGR gene in HT-29 human colon carcinoma cells binds IRF-1 following the stimulation of IFNγ to enhance the transcription of pIgR ( 43 ). It was confirmed that IRF-1 has important role in regulating the transcription of pIgR gene in intestinal epithelial cells both in vivo and in vitro stimulated by IFNγ ( 44 , 45 ), and the mRNA level of pIgR was greatly reduced in the intestines and liver of IRF-1-deficient mice ( 44 ). IFNγ usually stimulates the transcription of IRF-1 through activating STAT1 in the intestinal epithelium ( 25 , 46 ).…”