To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Abstract

Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation–associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell’s repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

“…Alu elements (AE) form one class where nucleolus formation depends on these elements [ 21 ]. AE inverted repeats can fold back on themselves and base-pair to form a double-stranded RNA that can form either left-handed Z-RNA or right-handed A-RNA, affecting the induction of interferon responses through the assembly of melanoma differentiation-associated gene 5 (MDA5, encoded by IFIH1) into filaments [ 22 ].…”

“…Z-RNA regulates both type I interferon responses by adenosine deaminase RNA specific (ADAR1, encoded by ADAR) [ 22 ] and the programmed cell death necroptosis pathway by Z-DNA binding protein 1 (ZBP1) [ 44 ]. In both cases, the left-handed helix is recognized by a structure specific, winged helix-turn-helix Zα protein domain without any base-specific contacts involved [ 45 , 46 ].…”

“…The scaffolds nucleated by double-stranded RNAs can be prion like, such as those observed for MDA5, and induce a type I interferon response [ 76 ]. The formation of Z-RNA by Alu inverted repeats within host sequences provides a mechanism to localize the double-stranded editing enzyme ADAR1 to terminate responses against self-RNAs [ 22 ]. Stress granules represent reversible protein aggregates, where it is proposed that interactions between RNAs and RRMs in proteins with prion-like domains prevent the formation of insoluble accretions [ 19 ].…”

Deciphering the Biological Significance of ADAR1–Z-RNA Interactions

“…Therefore, although binding to Z-DNA may play a biological function under certain conditions [ 69 ], it is reasonable to postulate that this domain plays a role in RNA regulation. Indeed, Zα of ADAR1 p150 efficiently binds to Z-RNA composed of CG repeats [ 59 , 70 , 71 ] ( Figure 4 ). Additionally, although in vivo Z-RNA sequences remain unknown, the addition of CG repeats to dsRNA increases ADAR1 p150-mediated RNA editing in vitro, which suggests Z-RNA formation affects the efficiency of RNA editing [ 72 ].…”

Special Issue: A, B and Z: The Structure, Function and Genetics of Z-DNA and Z-RNA

“…A number of themes emerged from the presentations and follow-up discussions. Based on presentations by Yukio Kawahara [ 11 ], Alan Herbert [ 12 ], Tony Sun [ 13 ] and Qingde Wang [ 14 ], the key role of ADAR1 p150, which contains the Z-DNA and Z-RNA binding Zα domain in regulating type I interferon responses in both human and mice, is now beyond doubt. The Kawahara lab has constructed a mouse model that expresses the ADAR p150 isoform that contains the Zα domain, but not the shorter p110 isoform.…”