BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K

Sang Won Park; Hilde Herrema; Mario Salazar; Isin Cakir; Serkan Cabi; Fatma Basibuyuk Sahin; Yu-Hsin Chiu; Lewis C Cantley; Umut Ozcan

doi:10.1016/j.cmet.2014.04.006

BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K

Cell Metab. 2014 Jul 1;20(1):73-84. doi: 10.1016/j.cmet.2014.04.006. Epub 2014 May 15.

Authors

Sang Won Park¹, Hilde Herrema², Mario Salazar², Isin Cakir², Serkan Cabi², Fatma Basibuyuk Sahin², Yu-Hsin Chiu³, Lewis C Cantley⁴, Umut Ozcan⁵

Affiliations

¹ Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: sangwon.park@childrens.harvard.edu.
² Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Department of System Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
⁴ 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.
⁵ Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: umut.ozcan@childrens.harvard.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line
Cell Nucleus / metabolism
Chromosomal Proteins, Non-Histone / antagonists & inhibitors
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism*
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / metabolism*
Endoplasmic Reticulum Stress
Glucose / metabolism*
HEK293 Cells
Humans
Liver / metabolism
Male
Mice
Mice, Obese
Phosphatidylinositol 3-Kinase / chemistry
Phosphatidylinositol 3-Kinase / deficiency
Phosphatidylinositol 3-Kinase / metabolism*
Protein Subunits / chemistry
Protein Subunits / deficiency
Protein Subunits / metabolism
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Regulatory Factor X Transcription Factors
Transcription Factors / chemistry
Transcription Factors / metabolism*
X-Box Binding Protein 1

Substances

Brd7 protein, mouse
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Protein Subunits
RNA, Messenger
RNA, Small Interfering
Regulatory Factor X Transcription Factors
Transcription Factors
X-Box Binding Protein 1
XBP1 protein, human
Xbp1 protein, mouse
Phosphatidylinositol 3-Kinase
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding