SANTOS A, Pal S, Chacon J, Meraz K, et al. SUMOylation affects the interferon blocking activity of the influenza A non-structural protein NS1 without affecting its stability or cellular localization. J Virol. 2013 Mar 6
Our pioneering studies on the interplay between the Small Ubiquitin-like MOdifier (SUMO) and influenza A virus identified the non-structural NS1 protein as the first known SUMO target of influenza virus and one of the most abundantly SUMOylated influenza proteins. Here, we further characterize the role of SUMOylation for the A/Puerto Rico/8/1934 (PR8) NS1 protein, demonstrating that NS1 is SUMOylated not only by SUMO1 but also by SUMO2/3, and mapping the main SUMOylation sites in NS1 to residues K219 and K70. Furthermore, by using SUMOylatable and non-SUMOylatable forms of NS1, and an NS1-specific Artificial SUMO Ligase (ASL) that increases NS1 SUMOylation ~4 fold, we demonstrate that SUMOylation does not affect the stability or cellular localization of PR8 NS1. However, NS1´s ability to be SUMOylated appears to affect viral multiplication, as indicated by the delayed growth of a virus expressing the non-SUMOylatable form of NS1 in the interferon (IFN)-competent MDCK cell line. Remarkably, while a non-SUMOylatable form of NS1 exhibited a substantially diminished ability to neutralize IFN production, increasing NS1 SUMOylation beyond its normal levels also exerted a negative effect on its IFN-blocking function. This observation indicates the existence of an optimal level of NS1 SUMOylation that allows NS1 to achieve maximal activity, and suggests that the limited amount of SUMOylation normally observed for most SUMO targets may correspond to an optimal level that maximizes the contribution of SUMOylation toward protein function. Finally, protein crosslinking data suggest that SUMOylation may affect NS1 function by regulating the abundance of NS1 dimers and trimers in the cell.
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