Catalytic activity of the proteasome fine-tunes Brg1-mediated chromatin remodeling to regulate the expression of inflammatory genes.

ABSTRACT

The induction of key pro-inflammatory genes is regulated by the SWI/SNF class of ATP-dependent remodeling complexes. In particular, the catalytic ATPase subunit, Brg1, is distinctly involved in the chromatin remodeling required for activating pro-inflammatory genes in a temporally, ordered fashion. Despite advances in our understanding of the role for Brg1 in the kinetics of inflammatory responses, little is known about the precise mechanisms which down-regulate Brg1 activity. Biochemical studies implicate a role for the proteasome in the regulation of SWI/SNF assembly and function; however, it is unclear if proteasome-dependent mechanisms modulate its remodeling activity or recruitment to chromatin in order to regulate inflammatory gene transcription. We now demonstrate for the first time that proteasome function represents an important mechanism for limiting inducible association of Brg1 with promoters of SWI/SNF-regulated, inflammatory genes. As a result, catalytic activity of the proteasome fine-tunes the kinetics of inflammatory gene transcription by inhibiting both premature and persistent chromatin remodeling at SWI/SNF-regulated genes. These results provide mechanistic insight into the interplay between nucleosome remodeling, inflammation and proteasome, and underscore the critical role of the proteasome in controlling both extent and duration of inflammatory responses.