P100/I?B? sequesters and inhibits NF-?B through kappaBsome formation.

ABSTRACT: Degradation of I kappaB (?B) inhibitors is critical to activation of dimeric transcription factors of the NF-?B family. There are two types of I?B inhibitors: the prototypical I?Bs (I?B?, I?B?, and I?B?), which form low-molecular-weight (MW) I?B:NF-?B complexes that are highly stable, and the precursor I?Bs (p105/I?B? and p100/I?B?), which form high-MW assemblies, thereby suppressing the activity of nearly half the cellular NF-?B [Savinova OV, Hoffmann A, Ghosh G (2009) Mol Cell 34(5):591-602]. The identity of these larger assemblies and their distinct roles in NF-?B inhibition are unknown. Using the X-ray crystal structure of the C-terminal domain of p100/I?B? and functional analysis of structure-guided mutants, we show that p100/I?B? forms high-MW (I?B?)4:(NF-?B)4 complexes, referred to as kappaBsomes. These I?B?-centric "kappaBsomes" are distinct from the 2:2 complexes formed by I?B?. The stability of the I?B? tetramer is enhanced upon association with NF-?B, and hence the high-MW assembly is essential for NF-?B inhibition. Furthermore, weakening of the I?B? tetramer impairs both its association with NF-?B subunits and stimulus-dependent processing into p52. The unique ability of p100/I?B? to stably interact with all NF-?B subunits by forming kappaBsomes demonstrates its importance in sequestering NF-?B subunits and releasing them as dictated by specific stimuli for developmental programs.

SUBMITTER: Tao Z 

PROVIDER: S-EPMC4234596 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature