Stability of the Rel homology domain is critical for generation of NF-κB p50 subunit

The NF-κB transcription factor p50 and the Rel protein-specific transcription inhibitor p105 are both encoded by the nfkb1 gene. The p50 protein is incorporated within the N-terminal portion of p105 and is a unique product of proteasomal processing. Because proteasome-mediated proteolysis generally results in complete degradation of the substrate, how p50 survives the proteasomal processing remains unknown. Survival of proteasomal processing has also been observed recently for the yeast transcription factors SPT23 and MGA2, but the mechanism is also unclear. Here we show evidence that stability of the Rel homology domain (RHD) within the N-terminal portion of the NF-κB 1 protein is required for p50 generation. We demonstrated that proteolysis initiated at an internal location of the NF-κB 1 protein, which normally generates p50, degrades the N-terminal portion of the NF-κB 1 protein when the RHD is destabilized. Our findings highlight the critical role of the unique structure of the RHD for the survival of p50 during proteosomal processing.