The Role of the Z-DNA Binding Domain in Innate Immunity and Stress Granules.

De Chen Chiang,Yan Li,Siew Kit Ng

doi:10.3389/fimmu.2020.625504

Abstract

Both DNA and RNA can maintain left-handed double helical Z-conformation under physiological condition, but only when stabilized by Z-DNA binding domain (ZDBD). After initial discovery in RNA editing enzyme ADAR1, ZDBD has also been described in pathogen-sensing proteins ZBP1 and PKZ in host, as well as virulence proteins E3L and ORF112 in viruses. The host-virus antagonism immediately highlights the importance of ZDBD in antiviral innate immunity. Furthermore, Z-RNA binding has been shown to be responsible for the localization of these ZDBD-containing proteins to cytoplasmic stress granules that play central role in coordinating cellular response to stresses. This review sought to consolidate current understanding of Z-RNA sensing in innate immunity and implore possible roles of Z-RNA binding within cytoplasmic stress granules.

Highlights

Z-DNA/Z-RNA and Za DomainThe structure of double-stranded DNA in nature can be broadly categorized into 3 major forms, namely compact right-handed A-DNA, loose right-handed B-DNA and the unique lefthanded Z-DNA conformation
We focused on the current understanding for the role of Za-containing proteins in innate immunity and posttranscriptional regulations, through their interaction with cytosolic Z-RNA
ZaE3L likely plays a role in competitive inhibition for Z-DNA/Z-RNA binding antagonizing the function of ADAR1p150 and ZDNA Binding Protein 1 (ZBP1) during virus infection [114]

Summary

Introduction

Z-DNA/Z-RNA and Za DomainThe structure of double-stranded DNA (dsDNA) in nature can be broadly categorized into 3 major forms, namely compact right-handed A-DNA, loose right-handed B-DNA and the unique lefthanded Z-DNA conformation. ADAR1 knockout studies showcased the vital regulatory role of ADAR1p150 in antiviral immune homeostasis and autoimmunity, through MDA5-MAVS sensing pathway [74], NF-kB gene regulation pathway [75] and PKR-mediated apoptosis [76] (Figure 2). ADAR1-kd cells exhibit an increase in SGs formation following virus infection or IFN-treatment, suggesting inhibitory role of ADAR1 on SGs formation [93].This is in line with the general observation whereby ADAR1 functions as a suppressor of type I interferon response, including inhibiting the PKR phosphorylation precluding SGs formation [77].

Results

Conclusion