TY - JOUR
T1 - GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling
AU - Tollenaere, Maxim A X
AU - Tiedje, Christopher
AU - Rasmussen, Simon
AU - Nielsen, Julie C
AU - Vind, Anna C
AU - Blasius, Melanie
AU - Batth, Tanveer S
AU - Mailand, Niels
AU - Olsen, Jesper V
AU - Gaestel, Matthias
AU - Bekker-Jensen, Simon
PY - 2019/3/26
Y1 - 2019/3/26
N2 - 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. 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.
AB - 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. 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.
U2 - 10.1016/j.celrep.2019.03.006
DO - 10.1016/j.celrep.2019.03.006
M3 - Journal article
C2 - 30917308
SN - 2211-1247
VL - 26
SP - 3511-3521.e4
JO - Cell Reports
JF - Cell Reports
IS - 13
ER -