The 20S proteasome processes NF-kappaB1 p105 into p50 in a translation-independent manner.
The NF-kappaB p50 is the N-terminal processed product of the precursor, p105. It has been suggested that p50 is generated not from full-length p105 but cotranslationally from incompletely synthesized molecules by the proteasome. We show that the 20S proteasome endoproteolytically cleaves the fully synthesized p105 and selectively degrades the C-terminus of p105, leading to p50 generation in a ubiquitin-independent manner. As small as 25 residues C-terminus to the site of processing are sufficient to promote processing in vivo. However, any p105 mutant that lacks complete ankyrin repeat domain (ARD) is processed aberrantly, suggesting that native processing must occur from a precursor, which extends beyond the ARD. Remarkably, the mutant p105 that lacks the internal region including the glycine-rich region (GRR) is completely degraded by 20S proteasome in vitro. This suggests that the GRR impedes the complete degradation of the p105 precursor, thus contributing to p50 generation.
Moorthy
Anu K
AK
Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, 92093, USA.
Savinova
Olga V
OV
Ho
Jessica Q
JQ
Wang
Vivien Ya-Fan
VY
Vu
Don
D
Ghosh
Gourisankar
G
D000818:Animals; D017089:Ankyrin Repeat / Q000235:genetics; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
D052002:NF-kappa B p50 Subunit; D025801:Ubiquitin; C073701:Nfkb1 protein, mouse; D046988:Proteasome Endopeptidase Complex; D005998:Glycine