KLF4 activates NFκB signaling and esophageal epithelial inflammation via the Rho-related GTP-binding protein RHOF.

Khvaramze Shaverdashvili,Amanda B Muir,John P Lynch,Jonathan P Katz,Divya Rao,Yang Jia,Kelly A Whelan,Jennie Padlo,Dorottya Laczkó,Wenpeng Jiang,Daniel Weinblatt,Claudia D Andl

doi:10.1371/journal.pone.0215746

Khvaramze Shaverdashvili, Amanda B Muir + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0215746

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Abstract

Understanding the regulatory mechanisms within esophageal epithelia is essential to gain insight into the pathogenesis of esophageal diseases, which are among the leading causes of morbidity and mortality throughout the world. The zinc-finger transcription factor Krüppel-like factor (KLF4) is implicated in a large number of cellular processes, such as proliferation, differentiation, and inflammation in esophageal epithelia. In murine esophageal epithelia, Klf4 overexpression causes chronic inflammation which is mediated by activation of NFκB signaling downstream of KLF4, and this esophageal inflammation produces epithelial hyperplasia and subsequent esophageal squamous cell cancer. Yet, while NFκB activation clearly promotes esophageal inflammation, the mechanisms by which NFκB signaling is activated in esophageal diseases are not well understood. Here, we demonstrate that the Rho-related GTP-binding protein RHOF is activated by KLF4 in esophageal keratinocytes, leading to the induction of NFκB signaling. Moreover, RHOF is required for NFκB activation by KLF4 in esophageal keratinocytes and is also important for esophageal keratinocyte proliferation and migration. Finally, we find that RHOF is upregulated in eosinophilic esophagitis, an important esophageal inflammatory disease in humans. Thus, RHOF activation of NFκB in esophageal keratinocytes provides a potentially important and clinically-relevant mechanism for esophageal inflammation and inflammation-mediated esophageal squamous cell cancer.

Highlights

Provide an accurate summary of the background, research objectives, including details of the species or strain of animal used, key methods, principal findings and conclusions of the study
Comment on the study limitations including any potential sources of bias, any limitations of the animal model, and the imprecision associated with the results[2]
How, the findings of this study are likely to translate to other species or systems, including any relevance to human biology

Summary

Introduction

Provide an accurate summary of the background, research objectives, including details of the species or strain of animal used, key methods, principal findings and conclusions of the study. A. Include sufficient scientific background (including relevant references to previous work) to understand the motivation and context for the study, and explain the experimental approach and rationale. B. Explain how and why the animal species and model being used can address the scientific objectives and, where appropriate, the study’s relevance to human biology. Give brief details of the study design including: a.

Results

Conclusion