Saturday, June 5, 2021

Viral ADP-ribosyltransferases attach RNA chains to host protein

Katharina H&oumlfer, Maik Schauerte, Julia Grawenhoff, Alexander Wulf, Luisa M. Welp, Franziska A. Billau, Henning Urlaub, Andres J&aumlschke

bioRxiv 2021.06.04.446905; 


he mechanisms by which viruses hijack their host's genetic machinery are of enormous current interest. One mechanism is adenosine diphosphate (ADP) ribosylation, where ADP-ribosyltransferases (ARTs) transfer an ADP-ribose fragment from the ubiquitous coenzyme nicotinamide adenine dinucleotide (NAD) to acceptor proteins. When bacteriophage T4 infects Escherichia coli, three different ARTs reprogram the host's transcriptional and translational apparatus. Recently, NAD was identified as a 5'-modification of cellular RNA molecules in bacteria and higher organisms. Here, we report that bacteriophage T4 ARTs accept not only NAD, but also NAD-RNA as substrate, thereby covalently linking entire RNA chains to acceptor proteins in an "RNAylation" reaction. One of these ARTs, ModB, efficiently RNAylates its host protein target, ribosomal protein S1, at arginine residues and strongly prefers NAD-RNA over NAD. Mutation of a single arginine at position 139 abolishes ADP-ribosylation and RNAylation. Overexpression of mammalian ADP-ribosylarginine hydrolase 1 (ARH1), which cleaves arginine-phosphoribose bonds, shows a decelerated lysis of E. coli when infected with T4. Our findings not only challenge the established views of the phage replication cycle, but also reveal a distinct biological role of NAD-RNA, namely activation of the RNA for enzymatic transfer. Our work exemplifies the first direct connection between RNA modification and post-translational protein modification. As ARTs play important roles in different viral infections, as well as in antiviral defence by the host, RNAylation may have far-reaching implications.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...