BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K.
Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family that is known to play a role as tumor suppressors. Here, we show that BRD7 is a component of the unfolded protein response (UPR) signaling through its ability to regulate X-box binding protein 1 (XBP1) nuclear translocation. BRD7 interacts with the regulatory subunits of phosphatidylinositol 3-kinase (PI3K) and increases the nuclear translocation of both p85α and p85β and the spliced form of XBP1 (XBP1s). Deficiency of BRD7 blocks the nuclear translocation of XBP1s. Furthermore, our in vivo studies have shown that BRD7 protein levels are reduced in the liver of obese mice, and reinstating BRD7 levels in the liver restores XBP1s nuclear translocation, improves glucose homeostasis, and ultimately reduces the blood glucose levels in the obese and diabetic mouse models.
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: sangwon.park@childrens.harvard.edu.
Sang Won
SW
Park
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Hilde
H
Herrema
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mario
M
Salazar
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Isin
I
Cakir
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Serkan
S
Cabi
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Fatma
F
Basibuyuk Sahin
Department of System Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Yu-Hsin
YH
Chiu
Department of System Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; Department of Medicine, Weill Cornell Medical College, New York City, NY 10065, USA.
Lewis C
LC
Cantley
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: umut.ozcan@childrens.harvard.edu.
Umut
U
Ozcan
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D000071717:X-Box Binding Protein 1; D000092468:Bromodomain Containing Proteins
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D005947:Glucose; D058539:Phosphatidylinositol 3-Kinase; D021122:Protein Subunits; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C400206:Brd7 protein, mouse; D000092468:Bromodomain Containing Proteins; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse