Intracellular Mono-ADP-Ribosylation in Signaling and Disease

Abstract

A key process in the regulation of protein activities and thus cellular signaling pathways is the modification of proteins by post-translational mechanisms. Knowledge about the enzymes (writers and erasers) that attach and remove post-translational modifications, the targets that are modified and the functional consequences elicited by specific modifications, is crucial for understanding cell biological processes. Moreover detailed knowledge about these mechanisms and pathways helps to elucidate the molecular causes of various diseases and in defining potential targets for therapeutic approaches. Intracellular adenosine diphosphate (ADP)-ribosylation refers to the nicotinamide adenine dinucleotide (NAD⁺)-dependent modification of proteins with ADP-ribose and is catalyzed by enzymes of the ARTD (ADP-ribosyltransferase diphtheria toxin like, also known as PARP) family as well as some members of the Sirtuin family. Poly-ADP-ribosylation is relatively well understood with inhibitors being used as anti-cancer agents. However, the majority of ARTD enzymes and the ADP-ribosylating Sirtuins are restricted to catalyzing mono-ADP-ribosylation. Although writers, readers and erasers of intracellular mono-ADP-ribosylation have been identified only recently, it is becoming more and more evident that this reversible post-translational modification is capable of modulating key intracellular processes and signaling pathways. These include signal transduction mechanisms, stress pathways associated with the endoplasmic reticulum and stress granules, and chromatin-associated processes such as transcription and DNA repair. We hypothesize that mono-ADP-ribosylation controls, through these different pathways, the development of cancer and infectious diseases.

Keywords: ADP-ribosylation; DNA repair; NF-κB; cancer; endoplasmic reticulum; gene transcription; immunity; infection; signaling; stress.

Figure 1

Functions of mono-ADP-ribosylating ARTD (ADP-ribosyltransferase diphtheria toxin-like) enzymes and of mono-ADP-ribosylating Sirtuins in signaling. Nuclear functions have been reported for ARTD8, ARTD9, ARTD10, ARTD14 and for SIRT6. ARTD8 has been described to regulate Signal Transducer and Activator of Transcription (STAT) 6-dependent gene expression, whereas ARTD8 and ARTD9 influence STAT1-dependent gene expression. Besides regulating STAT transcription factors, ARTD8 as well as ARTD10 and SIRT6 have been linked to DNA damage repair. ARTD14 interferes with AHR/ARNT (aryl hydrocarbon receptor/AHR nuclear translocator) driven gene expression. Moreover, SIRT6 regulates retrotransposon silencing. ARTD15 is localized to either the nuclear envelope where it influences nuclear-cytoplasmic shuttling or to the endoplasmic reticulum (ER) where it controls the unfolded protein response by modification of IRE1α (inositol requiring enzyme 1) and PERK (protein kinase RNA-like ER kinase). ARTD7, ARTD8 and ARTD12 are associated with stress granule formation. In addition, ARTD12 localizes to the autophagy receptor p62 and might be a player in the regulation of the NF-κB signaling pathway. Similarly, ARTD10 co-localizes with p62 in an ubiquitin-dependent manner and represses NF-κB signaling. ARTD10, ARTD12 and ARTD14 have been suggested to inhibit translation as well as viral replication. SIRT4 is localized to mitochondria and regulates glutamate dehydrogenase (GDH) activity and glutamine metabolism. For more details see the text.