Exogenous #EBNA1 promotes #ImmunotherapyResistance by enhancing #ADAR1 translation via the IGF2BP3/EIF4G1 complex, suppressing #Interferon signaling and #ImmuneResponse in #EBV-associated cancers.

#STTT #OpenAccess: doi.org/10.1038/s413...

Inositol hexakisphosphate Functions as a Cofactor and Modulator of ADAR1 Activity Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a key post-transcriptional modification that regulates RNA splicing, stability, and translation. Dysregulation of ADAR activity caused by mutations in ADAR1 leads to Aicardi-Goutieres syndrome (AGS), an autoimmune disorder characterized by aberrant activation of Melanoma differentiation-associated protein 5 (MDA5) by self RNA and excessive type I interferon production. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Here, we show that ADAR1 protein levels and RNA editing activity in mammalian cells critically depend on the cofactor inositol hexakisphosphate (IP6). Using Inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, next-generation sequencing (NGS), and a cell-permeable IP6 prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. In vitro ADAR1 translation and RNA editing assays revealed that IP6 contributes to the folding and full catalytic activity of ADAR1, and that inositol pentakisphosphate (1,3,4,5,6-IP5) can partially substitute IP6 as a cofactor. Molecular dynamics simulations and biochemical analyses identified the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly governs Zn2+-ion positioning through interactions with key residues, including K1039 and N907. Notably, the AGS-associated N907S mutation impairs RNA editing, by altering IP6 coordination and introducing a more dynamic situation in the hydrogen-bonding network that linked IP6 and Zn2+-ion. Together, these findings identifies IP6 as an essential cofactor and regulator of ADAR1 activity and highlights cofactor availability and interaction networks as potential strategies for therapeutically modulating RNA editing in disease. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, Project-ID 369799452— TRR237 - A02, Project-ID 548714673, CIBSS – EXC-2189 – Project ID 390939984 Volkswagen Foundation, VW Momentum Grant 98604 Israel Science Foundation, 2637/23 Medical Research Council, MR/T028904/1

If you are interested in RNA editing, ADAR1, or inositol phosphates, you may find our new preprint of interest.
“Inositol hexakisphosphate functions as a cofactor and modulator of ADAR1 activity”
Preprint available on @biorxivpreprint.bsky.social
www.biorxiv.org/content/10.6...
#ADAR1 #RNAEditing

How do tiny molecules like #RNA control essential cellular functions?

Our #ResearcheroftheMonth Vinod Rajendra and his team uncovered how the protein #ADAR1 forms a functional pair — a key step in how it acts on RNA.

More details about their findings! ➡️ https://bit.ly/3XZisMF

#MedUniVienna

Zα and Zβ domains of ADAR1 and ZBP1 bind to G-quadruplexes with low micromolar affinity While it is well established that the Zα domains of ADAR1 and ZBP1 proteins bind Z-form prone nucleic acid, it has also been shown that the Zα domain of ADAR1 binds DNA G-quadruplexes. However, no bin...

We uncover the first evidence that the long-mysterious Zβ domain of #ADAR1 binds G-quads, a surprising twist that reshapes how we think about ADAR targeting—opening new directions for understanding the links between innate immunity and splicing regulation. #NMR #RNA
www.biorxiv.org/content/10.1...

New research reveals that 8-Cl-Ado inhibits #Hepatocarcinogenesis by suppressing #ADAR1 and regulating PPARγ-driven #LipidMetabolism, offering new #therapeutic targets for #HCC. #medsky

#OpenAccess: www.sciencedirect.com/science/arti...

Cancer cell and microenvironmental rewiring by ADAR1 loss impairs glioblastoma tumor growth and extends survival Álvarez-Prado et al. report that targeting ADAR1 triggers cancer-cell-intrinsic anti-proliferative mechanisms and fosters anti-tumoral immune responses, blocking tumor growth and extending survival in...

Can we exploit anti-viral immunity to treat brain cancer? 🦠 🧠

Our last results suggest so, go ahead and check the paper if you’re curious! 🤓

www.cell.com/cell-reports...

#Brain_cancer #Glioblastoma #TumorMicroenvironment #RNAsensing #ADAR1

#ADAR1 #RNA #Editing

Adipogen Life Sciences

System Vaccinology news on adipogen.com/news
Four studies in Cell Reports and Nature identify the #IFN-induced protein #ZBP1 as a key effector of #autoinflammatory #pathology induced by mutations of the Z-DNA-binding domain of #ADAR1, using the Gold Standard antibody #Zippy-1 #AdipoGen encr.pw/PtlK8