上海科技大学知识管理系统

The precursor of Sterol Regulatory Element Binding Protein-2 (SREBP2) is a membrane-bound transcription factor regulating cholesterol biosynthesis. Under cholesterol-deficient condition, the mature/ nuclear SREBP2 (nSREBP2) is released from membrane-bound precursor through proteolytic cleavage, enters nucleus and activates transcription of cholesterogenic genes. Previous studies have illustrated the processes of SREBP cleavage. However, how the transcription activity of nSREBP2 is regulated in nucleus is poorly understood. Here, we report that the nSREBP2 forms discrete nuclear condensates through its N-terminal intrinsically disordered region (IDR) and works together with transcription coactivators BRD4 and p300, partly on super-enhancers, for the transcriptional activation of SREBP2 target genes. The substitution of a critical and conserved phenylalanine (F) to alanine (A) within the IDR abolishes the formation of nSREBP2 condensates. Conversely, the condensate formation and efficient transcription activation are rescued by fusion with a phase separation driving FUS-IDR. Knock-in of the F to A substitution in mice compromises the feeding-induced nSREBP2 activity and lowers the cholesterol levels, underscoring the functional significance of nSREBP2 condensates. Together, this study reveals that nuclear condensates driven by the N terminal IDR of nSREBP2 facilitate the efficient activation of lipogenic genes and play an important role in cholesterol homeostasis.