title: Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10.
abstract: Adenosine diphosphate-ribosylation is a post-translational modification mediated by intracellular and membrane-associated extracellular enzymes and many bacterial toxins. The intracellular enzymes modify their substrates either by poly-ADP-ribosylation, exemplified by ARTD1/PARP1, or by mono-ADP-ribosylation. The latter has been discovered only recently, and little is known about its physiological relevance. The founding member of mono-ADP-ribosyltransferases is ARTD10/PARP10. It possesses two ubiquitin-interaction motifs, a unique feature among ARTD/PARP enzymes. Here, we find that the ARTD10 ubiquitin-interaction motifs bind to K63-linked poly-ubiquitin, a modification that is essential for NF-κB signalling. We therefore studied the role of ARTD10 in this pathway. ARTD10 inhibits the activation of NF-κB and downstream target genes in response to interleukin-1β and tumour necrosis factor-α, dependent on catalytic activity and poly-ubiquitin binding of ARTD10. Mechanistically ARTD10 interferes with poly-ubiquitination of NEMO, which interacts with and is a substrate of ARTD10. Our findings identify a novel regulator of NF-κB signalling and provide evidence for cross-talk between K63-linked poly-ubiquitination and mono-ADP-ribosylation.
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen 52074, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Verheugd
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Forst
authors.forename: Larissa
authors.initials: L
authors.lastname: Milke
authors.forename: Nicolas
authors.initials: N
authors.lastname: Herzog
authors.forename: Karla L H
authors.initials: KL
authors.lastname: Feijs
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Henning
authors.initials: H
authors.lastname: Kleine
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; D036002:ADP Ribose Transferases