SUMOylation attenuates the transcriptional activity of the NF-κB subunit RelB.

The NF-κB subunit RelB is known to act either as an activator or repressor of NF-κB-dependent gene expression. The RelB-p52 heterodimer, for instance, is the key element of the alternative NF-κB signaling pathway supporting the expression of a subset of NF-κB target genes. By contrast, RelB is crucial for the repression of important pro-inflammatory cytokines like TNFα or interleukin 1ß. Despite accumulating reports describing the functional variability of RelB, the molecular mechanisms underlying these divergent functions are still unknown. One potential explanation could be a functional reprogramming of RelB by different post-translational modifications. Here, we demonstrate that SUMOylation of RelB might be one of these post-translational modifications rendering the function of the NF-κB transcription factor RelB. In vivo SUMOylation analyses using either the UBC9-fusion-directed SUMOylation method or endogenous proteins from Namalwa B cells revealed that RelB is modified by either SUMO1 or SUMO2 attachment at various sites. Functional studies suggest that SUMOylation converts RelB into a transcriptional repressor. For instance, a SUMO1-RelB fusion protein mimicking RelB-SUMOylation displayed a reduced transcriptional activity in comparison to wild type RelB. Consistently, inactivation of specific SUMOylation sites in the central part of RelB augmented the transcription activity of the corresponding RelB mutant. Taken together, our data suggest that SUMOylation might be a potential molecular mechanism involved in reprogramming RelB, thus contributing to its functional diversity.