Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

Abstract

In response to excessive nucleotide-binding oligomerization domain–containing protein 2 (Nod2) stimulation caused by mucosal bacterial components, gut epithelia need to activate regulatory machinery to maintain epithelial homeostasis. Activating transcription factor 3 (ATF3) is a representative regulator in the negative feedback loop that modulates TLR-associated inflammatory responses. In the current study, the regulatory effects of ribosomal stress-induced ATF3 on Nod2-stimulated proinflammatory signals were assessed. Ribosomal inactivation caused persistent ATF3 expression that in turn suppressed proinflammatory chemokine production facilitated by Nod2. Decreased chemokine production was due to attenuation of Nod2-activated NF-κB and early growth response protein 1 (EGR-1) signals by ATF3. However, the underlying molecular mechanisms involve two convergent regulatory pathways. Although ATF3 induced by ribosomal inactivation regulated Nod2-induced EGR-1 expression epigenetically through the recruitment of histone deacetylase 1, NF-κB regulation was associated with posttranscriptional regulation by ATF3 rather than epigenetic modification. ATF3 induced by ribosomal inactivation led to the destabilization of p65 mRNA caused by nuclear entrapment of transcript-stabilizing human Ag R protein via direct interaction with ATF3. These findings demonstrate that ribosomal stress-induced ATF3 is a critical regulator in the convergent pathways between EGR-1 and NF-κB, which contributes to the suppression of Nod2-activated proinflammatory gene expression.

Deoxynivalenol Impairs Porcine Intestinal Host Defense Peptide Expression in Weaned Piglets and IPEC-J2 Cells

“…The inhibitory effect of DON on NOD2 expression was also demonstrated by the present in vitro study. This result is consistent with data from human enterocytes [19].…”

Deoxynivalenol Impairs Porcine Intestinal Host Defense Peptide Expression in Weaned Piglets and IPEC-J2 Cells

“…The inhibitory effect of DON on NOD2 expression was also demonstrated by the present in vitro study. This result is consistent with data from human enterocytes [19].…”

ATF3 inhibits the inflammation induced byMycoplasma pneumoniain vitro and in vivo

“…In addition, the overexpression of ATF3 resulted in the suppression of Egr‐1 and Fyn expression in RAW264.7; conversely, depletion of ATF3 increased the protein levels of Egr‐1 and Fyn, this results is supported by a previous study demonstrating that ATF3 can suppress Egr‐1 expression . Furthermore, our data confirmed that the anti‐inflammation effect of ATF3 was abrogated after forcing expression of Egr‐1 in RAW264.7, which was supported by the observation that decreased chemokine production was due to the attenuation of Egr‐1 by ATF3 in human intestinal epithelium . In addition, recent studies have revealed that the anti‐inflammatory effect of docosahexaenoic acid on the endothelium is associated with the downregulation of Egr‐1 .…”

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

“…To speculate the molecular mechanism of nuclear entrapment of HuR under ribosomal inactivation, we confirmed the known interaction between HuR and nuclear ATF3 in the present model (Supplemental Fig. 1), based on our previous report (50). ATF3 as a transcription factor was induced and translocated into nuclei by ribosomal inactivation (Supplemental Fig.…”

Deoxynivalenol Impairs Porcine Intestinal Host Defense Peptide Expression in Weaned Piglets and IPEC-J2 Cells

“…The inhibitory effect of DON on NOD2 expression was also demonstrated by the present in vitro study. This result is consistent with data from human enterocytes [19].…”

ATF3 inhibits the inflammation induced byMycoplasma pneumoniain vitro and in vivo

“…In addition, the overexpression of ATF3 resulted in the suppression of Egr‐1 and Fyn expression in RAW264.7; conversely, depletion of ATF3 increased the protein levels of Egr‐1 and Fyn, this results is supported by a previous study demonstrating that ATF3 can suppress Egr‐1 expression . Furthermore, our data confirmed that the anti‐inflammation effect of ATF3 was abrogated after forcing expression of Egr‐1 in RAW264.7, which was supported by the observation that decreased chemokine production was due to the attenuation of Egr‐1 by ATF3 in human intestinal epithelium . In addition, recent studies have revealed that the anti‐inflammatory effect of docosahexaenoic acid on the endothelium is associated with the downregulation of Egr‐1 .…”

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

“…To speculate the molecular mechanism of nuclear entrapment of HuR under ribosomal inactivation, we confirmed the known interaction between HuR and nuclear ATF3 in the present model (Supplemental Fig. 1), based on our previous report (50). ATF3 as a transcription factor was induced and translocated into nuclei by ribosomal inactivation (Supplemental Fig.…”

Deoxynivalenol Impairs Porcine Intestinal Host Defense Peptide Expression in Weaned Piglets and IPEC-J2 Cells

“…The inhibitory effect of DON on NOD2 expression was also demonstrated by the present in vitro study. This result is consistent with data from human enterocytes [19].…”

ATF3 inhibits the inflammation induced byMycoplasma pneumoniain vitro and in vivo

“…In addition, the overexpression of ATF3 resulted in the suppression of Egr‐1 and Fyn expression in RAW264.7; conversely, depletion of ATF3 increased the protein levels of Egr‐1 and Fyn, this results is supported by a previous study demonstrating that ATF3 can suppress Egr‐1 expression . Furthermore, our data confirmed that the anti‐inflammation effect of ATF3 was abrogated after forcing expression of Egr‐1 in RAW264.7, which was supported by the observation that decreased chemokine production was due to the attenuation of Egr‐1 by ATF3 in human intestinal epithelium . In addition, recent studies have revealed that the anti‐inflammatory effect of docosahexaenoic acid on the endothelium is associated with the downregulation of Egr‐1 .…”

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

“…To speculate the molecular mechanism of nuclear entrapment of HuR under ribosomal inactivation, we confirmed the known interaction between HuR and nuclear ATF3 in the present model (Supplemental Fig. 1), based on our previous report (50). ATF3 as a transcription factor was induced and translocated into nuclei by ribosomal inactivation (Supplemental Fig.…”