Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity

Sanjeev Choudhary, Istvan Boldogh, Allan R. Brasier

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries about 2 nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP-lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1:8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the nuclear factor (NF)κB/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type I and type III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in pattern recognition receptor signaling, regulating the IIR.

Original languageEnglish (US)
JournalJournal of Innate Immunity
DOIs
StateAccepted/In press - Jan 13 2016

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Innate Immunity
Reactive Oxygen Species
Ataxia Telangiectasia
Lung
Cell Nucleus Active Transport
Transcription Factor RelA
Phosphorylation
DNA-(Apurinic or Apyrimidinic Site) Lyase
Ribosomal Protein S6 Kinases
Guanine Nucleotide Exchange Factors
Pattern Recognition Receptors
CXC Chemokines
CC Chemokines
Interferon Type I
Immediate-Early Genes
Monomeric GTP-Binding Proteins
Gene Regulatory Networks
Guanine
Adaptive Immunity
Phosphatidylinositol 3-Kinases

ASJC Scopus subject areas

  • Immunology and Allergy

Cite this

Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity. / Choudhary, Sanjeev; Boldogh, Istvan; Brasier, Allan R.

In: Journal of Innate Immunity, 13.01.2016.

Research output: Contribution to journalArticle

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