RNA-Binding Protein Isoforms ZAP-S and ZAP-L Have Distinct Antiviral and Immune Resolution Functions
This week we profile a recent publication in Nature Immunology from Dr. Johannes
Schwerk (pictured) in the laboratory of Dr. Ram Savan at the UW School of Medicine.
Can you provide a brief overview of your lab’s current research focus?
Genetic variations in the non-coding regions of RNA dictate susceptibility to viral infections. However, the underlying functional mechanisms are largely unknown. In Dr. Ram Savan’s lab, we focus on understanding how host genetic variations in the non-coding regions affect the innate immune responses to viral infections.
What is the significance of the findings in this publication?
Robust inflammatory responses are essential to control microbial infections. At the same time, it is critical to resolve inflammation to minimize tissue damage as a consequence of an overactive immune response. In our recent publication, we identified a host innate immune gene, zinc-finger antiviral protein (ZAP), that plays a dual role in clearing alphavirus infection and controlling interferon-induced inflammation. These distinct and rather disparate activities are determined by expression of two ZAP isoforms. The long isoform of ZAP is constitutively expressed and binds to the viral RNA, effectively blocking viral replication and dissemination. Interestingly, the short isoform of ZAP, which is induced later during infection, binds to and negatively regulates host interferon mRNA, thereby resolving the interferon-mediated immune response. A major question was how these two ZAP isoforms differentiate between self and non-self RNA, as both proteins harbor the same RNA recognition motif. We found that subcellular localization of the isoforms determined their specificity to host and viral RNAs. The long isoform of ZAP was post-translationally modified to contain a lipophilic tail, which targeted the protein to endolysosomal compartments. Interestingly, alphaviruses utilize endolysosomes for their replication. Placement of the long ZAP isoform to these viral replication complexes effectively neutralizes the virus. On the other hand, the short isoform of ZAP lacks the lipophilic tail and therefore is diffusely distributed within the cytosol. As the host interferon mRNA is localized in the cytosol, the short ZAP isoform can readily bind and negatively regulate it. In conclusion, our study shows that through alternative polyadenylation and differential post-translational modification, a single immune gene can be diversified to perform differential functions.
What are the next steps for this research?
Our lab is currently investigating if the host is – similar to our findings on ZAP – diversifying innate immune gene functions to tackle microbial infections through alternative splicing and post-translational modifications of other antiviral proteins. Furthermore, we are testing if genetic variations in the non-coding regions are governing generation of different antiviral protein isoforms to determine if viral susceptibility is based on such genetic variations.
This work was funded by:
This study was carried out in collaboration with the laboratories of Dr. Matthew Daugherty (UCSD), Dr. Michael Gale jr. (UW Immunology), and Dr. Jennifer Hyde (UW Microbiology). This work was funded by a Postdoctoral Research Fellowship from the German Research Foundation, as well as by NIH grants AI108765, AI135437, AI119017, AI104002, AI118916, AI127463, AI106677, GM007270, and GM007240.