Résumé
SUMOylation is the post-translational covalent but reversible conjugation of SUMO to proteins. In human, the SUMO protein family consists of SUMO1 and two highly homologous proteins SUMO2 and SUMO3 (collectively called SUMO2/3), which cannot be distinguished by currently available antibodies. We have shown that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation resulting in an inhibition of IFNγ-induced transcription without affecting that of IFNα. Here, we focused on the IFN-induced gene products associated with PML nuclear bodies and we show that in SUMO3-expressing cells, neither IFNα nor IFNγ could increase PML and Sp100 protein expression, as they enhanced their SUMO3 conjugation and subsequent proteasomal degradation. Since it is known that SUMO3 is important for the recruitment of RNF4, a poly-SUMO-dependent E3 ubiquitin ligase implicated in PML degradation in arsenic-treated cells, we went on to show that RNF4 depletion in IFN-treated HeLa-SUMO3 cells prevented PML degradation, thus restoring an increase of PML and Sp100 protein expression in response to IFN. In addition, SUMO3, but not SUMO1, overexpression reduced the capacity of IFN to inhibit viral proteins and EMCV production. These results are consistent with the degradation of PML in IFN-treated HeLa-SUMO3 cells, and with our previous observation that PML depletion decreases the anti-EMCV effect of IFN (Maroui et al., J Virol 2011).
Altogether, our results uncover a new role for SUMO3 in the modulation of both type I and type II IFN responses.