GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling

• Published in: Cell reports (Cambridge) 2019-03, Vol.26 (13), p.3511-3521.e4
• Main Authors: Tollenaere, Maxim A.X., Tiedje, Christopher, Rasmussen, Simon, Nielsen, Julie C., Vind, Anna C., Blasius, Melanie, Batth, Tanveer S., Mailand, Niels, Olsen, Jesper V., Gaestel, Matthias, Bekker-Jensen, Simon
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Carrier Proteins - metabolism; Cell Line, Tumor; Cytokines - metabolism; Humans; Inflammation - genetics; Inflammation - metabolism; Protein Binding; RNA Processing, Post-Transcriptional; RNA, Messenger - metabolism; Signal Transduction; Tristetraprolin - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.03.006

Inflammatory signaling is restricted through degradation and the translational repression of cytokine mRNAs. A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs. Here, we show that the RBP ZNF598 contributes to the same regulatory module in a TTP-like manner. Similar to TTP, ZNF598 harbors three proline-rich motifs that bind the GYF domain of GIGYF1. RNA sequencing experiments showed that ZNF598 is required for the regulation of known TTP targets, including IL-8 and CSF2 mRNA. Furthermore, we demonstrate that ZNF598 binds to IL-8 mRNA, but not TNF mRNA. Collectively, our findings highlight that ZNF598 functions as an RBP that buffers the level of a range of mRNAs. We propose that ZNF598 is a TTP-like factor that can contribute to the regulation of the inflammatory potential of cytokine-producing cells. [Display omitted] •Proline stretches in ZNF598 are bound by the GYF domain of GIGYF1 and GIGYF2•GIGYF1/2 interaction integrates ZNF598 into a complex that represses mRNA translation•ZNF598 binds to and regulates the abundance of inflammation-associated mRNA transcripts•The mRNA-binding repertoire of ZNF598 partially overlaps that of TTP/ZFP36 Tollenaere et al. highlight a structural and functional resemblance between the ribosome-associated ubiquitin ligase ZNF598 and TTP, the negative regulator of inflammation-associated mRNA stability. Like TTP, ZNF598 contains proline stretches that are bound by GYF domain-containing proteins, binds cytokine mRNAs, and represses inflammatory signaling in resting cells.