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

Further ARTD10, ARTD12 and ARTD14 downregulate cellular translation in cells infected with 342 VEEV, which in the case of ARTD12 depends on catalytic activity [8] . ARTD12 has also been 343 identified to restrict Zika virus (ZIKV) replication, which is mediated by depletion of the ZIKV 344 non-structural proteins NS1 and NS3 [26] . Dependent on its catalytic activity, ARTD12 seems 345 to promote poly-ADP-ribosylation (PARylation) of these two viral proteins. PAR chains in turn 346 are argued to serve as scaffold to recruit E3 Ubiquitin-ligases that modify NS1 and NS3 by K48-347 linked polyubiquitination and thereby enable their proteasomal degradation [26] . Indeed, this 348 concept has already been established for PARylation mediated by ARTD5 and 6 (tankyrase 1 349 and 2, respectively) [1]. More than 70 substrates have been identified to be regulated through 350 PAR-mediated poly-ubiquitination [54] . The proposed mechanism is that ARTD12, as it is 351 limited to MARylation, modifies NS1 and NS3, which serves as a seeding event for polymer 352 forming ARTDs, possibly ARTD5 or 6 [26] . However, the effect of MARylation on CHIKV 353 replication seems to be different as demonstrated by experiments with inhibitors of 354 proteasomal and lysosomal pathways in this study (Fig. 3a,b) . In addition to the ZIKV proteins, 355 the nucleocapsid protein of Coronavirus (CoV) was recently suggested to be ADP-ribosylated 356 . 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 It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the .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 during infection [55] . It will be interesting to identify the enzyme that catalyzes this 357 modification and moreover to define the molecular consequences, for example on capsid 358 formation. 359