Repression of Peroxisome Proliferator-Activated Receptor γ by Mucosal Ribotoxic Insult-Activated CCAAT/Enhancer-Binding Protein Homologous Protein

The Journal of Immunology

et al. 2013

Self Cite

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.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Park

Hun

The Journal of Immunology

et al. 2013

Self Cite

“…Mechanistically, chemical ribosomal stress alters intestinal mucosal integrity by interfering with transepithelial resistance, epithelial differentiation, and nutrient absorption, the last of which is associated with anorexia and weight loss (36)(37)(38)(39). Moreover, ribosomal stress triggers mucosal and systemic inflammation, mostly due to the enhanced production of proinflammatory mediators in immune-related cells (40)(41)(42)(43).…”

mentioning

confidence: 99%

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

Hun

The Journal of Immunology

Kim

et al. 2013

Self Cite

Although the activation of B cells in the gastrointestinal tract is of great importance in the context of immunity to pathogens and mucosal inflammatory diseases, little is known about the mechanisms responsible for the local activation of B cells in the subepithelial area of the intestine. Epithelium-derived BAFF is the major modulator of B cell development and Ig class switching. The present study was performed to address the molecular mechanism of BAFF expression in gut epithelial cells in the presence of proinflammatory stimuli. Inflammation-induced BAFF expression in mucosal epithelial cells might be responsible for diverse mucosa-associated diseases linked to intestinal inflammation and autoimmunity. Although BAFF was marginally expressed in unstimulated epithelial cells, BAFF mRNA was significantly upregulated by proinflammatory IFN-γ. Furthermore, IFN-γ triggered JAK/STAT1 signals via the cytokine receptor, which contributed to epithelial BAFF upregulation. In terms of signaling intervention, ribosomal insult attenuated IFN-γ–activated JAK/STAT signal transduction and subsequent BAFF induction in gut epithelial cells. Ribosomal insults led to the superinduction of SOCS3 by enhancing its mRNA stability via HuR RNA-binding protein. Upregulated SOCS3 then contributed to the blocking of the JAK/STAT-linked signal, which mediated BAFF suppression by ribosomal stress. All of these findings show that ribosomal stress–induced SOCS3 plays a novel regulatory role in epithelial BAFF production, suggesting that epithelial ribosomal dysfunction in association with SOCS3 may be a promising therapeutic point in BAFF-associated human mucosal diseases.

“…5A). Although PPAR␥ is generally involved in transcriptional regulation, it is also a critical player in posttranscriptional modulation by attenuating cytosolic translocation of HuR protein (29,30). When PPAR␥ expression was exogenously enhanced, ER stress-triggered cytosolic translocation of HuR protein was strongly attenuated (Fig.…”

Section: Chop Modulates In-and-out Behavior Of Hur Protein By Limitinmentioning

confidence: 99%

Two In-and-out Modulation Strategies for Endoplasmic Reticulum Stress-linked Gene Expression of Pro-apoptotic Macrophage-inhibitory Cytokine 1

Park

Journal of Biological Chemistry

Yang

et al. 2012

Self Cite

Background: Modulation of a pro-apoptotic MIC-1 was addressed under ER stress-linked alterations of intracellular components. Results: Transporting of transcript-associated complex across cellular compartments is critical for MIC-1 mRNA stabilization. Conclusion: Stabilization is due to complex formation with pumped-out RNA-binding protein and their timely exit from the stress granule. Significance: Harmonized in-and-out modulation implicates key regulatory processes of MIC-1 expression in ER stress-linked therapy and biology.