Mono-ADP-ribosylation by ARTD10 restricts Chikungunya virus replication by interfering with the proteolytic activity of nsP2

Sarah Krieg; Fabian Pott; Laura Eckei; Maud Verheirstraeten; Mareike Bütepage; Barbara Lippok; Christine Goffinet; Bernhard Lüscher; Patricia Verheugd

MARylation-dependent inhibition of the protease activity is antagonized by the macrodomain 328 of nsP3. Accordingly, the lack of MAR hydrolase activity prevents polyprotein processing. Thus, 329 our findings elucidate a mechanism for the importance of a functional macrodomain for CHIKV 330 replication. 331 332 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.01.07.896977 doi: bioRxiv preprint 15 ARTDs have been linked previously to restriction of virus replication [22] . In this context the 333 best studied ARTD family member is ARTD13 (ZAP, Zinc-finger antiviral protein), which is able 334 to bind viral RNA, promoting its decay or interfering with its translation [53] . Further, ARTD13, 335 which is catalytically inactive, contributes to the establishment of an antiviral immune 336 response by crosstalk with the miRNA pathway, thereby stimulating expression of antiviral 337 proteins, and by amplifying RIG-I signaling [53] . Antiviral activities have also been assigned to 338 ARTD10, ARTD12 and ARTD14. Overexpression of these ARTDs was shown to interfere with 339 Venezuelan equine encephalitis virus (VEEV) replication [7] . Additionally, ARTD12 was 340 described to restrict Sindbis Virus (SINV) and CHIKV replication amongst other RNA viruses [7] . 341