Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA sensing mechanism that activates MDA5-MAVS-IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, usually located in the nucleus, remains largely unknown. Here we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and export from the nucleus. Once translocated to the cytoplasm, ADAR1p110 suppresses apoptosis of stressed cells by protecting many anti-apoptotic gene transcripts that contain 3′UTR dsRNA structures primarily made from inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3′UTR dsRNAs and antagonizes the Staufen1-mediated mRNA decay. Our studies revealed a new stress response mechanism, in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA (dsRNA). Among the three types of mammalian ADARs, ADAR1 has long been recognized as an essential enzyme for normal development. The interferon-inducible ADAR1p150 is involved in immune responses to both exogenous and endogenous triggers, whereas the functions of the constitutively expressed ADAR1p110 are variable. Recent findings that ADAR1 is involved in the recognition of self versus non-self dsRNA provide potential explanations for its links to hematopoiesis, type I interferonopathies, and viral infections. Editing in both coding and noncoding sequences results in diseases ranging from cancers to neurological abnormalities. Furthermore, editing of noncoding sequences, like microRNAs, can regulate protein expression, while editing of Alu sequences can affect translational efficiency and editing of proximal sequences. Novel identifications of long noncoding RNA and retrotransposons as editing targets further expand the effects of A-to-I editing. Besides editing, ADAR1 also interacts with other dsRNA-binding proteins in editing-independent manners. Elucidating the disease-specific patterns of editing and/or ADAR1 expression may be useful in making diagnoses and prognoses. In this review, we relate the mechanisms of ADAR1′s actions to its pathological implications, and suggest possible mechanisms for the unexplained associations between ADAR1 and human diseases.

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Emphysema is a unique type of chronic obstructive pulmonary disease, and sex may influence susceptibility. After cigarette smoke exposure, murine males and ovariectomized females developed more severe emphysema. Herein, we present divergent bulk and single-cell transcriptomic profiles between male and female murine lungs. Weighted Gene Co-Expression Network Analysis of the bulk lung RNA sequencing identified a Green gene module that correlated with male sex and ovariectomy. The Green gene module was enriched in common monocyte progenitors, classical monocytes, type 1 dendritic cells, and macrophages from 83,698 murine cells exposed to air or cigarette smoke for five months. Sexual dimorphism altered the compositions and transcriptome of the clusters enriched with the Green gene module. This comprehensive transcriptomic analysis advances our understanding of dynamic cellular responses controlled by sexual dimorphism during the development of emphysematous pulmonary tissue remodeling and reveals potential targets for mechanistic studies in the future.