Poly(ADP-Ribose) Regulates Stress Responses and MicroRNA Activity in the Cytoplasm

Abstract

Summary Poly(ADP-ribose) is a major regulatory macromolecule in the nucleus, where it regulates transcription, chromosome structure and DNA damage repair. Functions in the interphase cytoplasm are less understood. Here we identify a requirement for poly(ADP-ribose) in the assembly of cytoplasmic stress granules, which accumulate RNA-binding proteins that regulate the translation and stability of mRNAs upon stress. We show that poly(ADP-ribose), 6 specific poly(ADP-ribose) polymerases and 2 poly(ADP-ribose) glycohydrolase isoforms are stress granule components. A subset of stress granule proteins, including microRNA-binding Argonaute family members Ago1-4, are modified by poly(ADP-ribose) and such modification increases upon stress – a condition when both microRNA-mediated translational repression and microRNA-directed mRNA cleavage are relieved. Similar relief of repression is also observed upon overexpression of specific poly(ADP-ribose) polymerases or, conversely, upon knockdown of glycohydrolase. We conclude that poly(ADP-ribose) is a key regulator of post-transcriptional gene expression in the cytoplasm.

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

“…S-Farnesylation of ZAPL but not ZAPS enhances the antiviral activity (18). Both ZAPL and ZAPS can be modified by poly(ADPribose) and such modification was proposed to participate in the regulation of microRNA-mediated gene silencing (14). Here, we report that TRIM25-mediated ubiquitination is required for the antiviral function of ZAP.…”

“…ZAP targets the 3=-untranslated region of TRAILR4 mRNA and promotes its degradation, thereby sensitizing cells to TRAIL-mediated apoptosis (13). ZAP interacts with Ago2 and regulates miRNA-mediated gene silencing (14).…”

mRNP granules

“…50 Such interactions also underpin recruitment of tudor-domain proteins to stress granules. 52,53 O-linked N-acetyl glucosamine, 53 poly (ADP) ribosylation, 54 acetylation, and ubiqutination 39 are also modifications present on specific stress granule components, which have been implicated in stress granule assembly, albeit the mechanisms are not entirely clear. Finally, the phosphorylation of several proteins, including G3BP, 29 TTP, 55 Dcp1, 42,56 Dcp2, 57 and 4E-T 58 alters their localization within, and/or the assembly of their respective granules.…”

Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform

“…In addition, ZAPS and ZAPL are both polyADP ribosylated and have been implicated in stabilization of mRNA during cellular stress (37). Interestingly, ZAPS polyADP ribosylation is selectively elevated during cellular stress compared with ZAPL (37). These results highlight a potential duality in the regulation and functions of ZAP isoforms.…”

“…hZAPS is also more active than hZAPL in enhancing RIG-Idependent signaling in response to 5′-triphosphate-modified RNA, suggesting that regulation of ZAP activity can enhance or even amplify IFN responses (36). In addition, ZAPS and ZAPL are both polyADP ribosylated and have been implicated in stabilization of mRNA during cellular stress (37). Interestingly, ZAPS polyADP ribosylation is selectively elevated during cellular stress compared with ZAPL (37).…”