title: ZNF70, a novel ILDR2-interacting protein, contributes to the regulation of HES1 gene expression.
abstract: A diabetes susceptibility gene, immunoglobulin-like domain containing receptor 2 (Ildr2), encodes a transmembrane protein localized to the endoplasmic reticulum membrane that is closely related to hepatic lipid metabolism. The livers of ob/ob mice in which Ildr2 is transiently overexpressed are relieved of hepatic steatosis. However, the molecular mechanisms through which ILDR2 affects these changes in hepatic lipid metabolism remain unknown. This study aimed to identify ILDR2-interacting proteins to further elucidate the molecular mechanisms underlying the role of ILDR2 in lipid homeostasis. We purified ILDR2-containing protein complexes using tandem affinity purification tagging and identified ZNF70, a member of the Kruppel C2H2-type zinc finger protein family, as a novel ILDR2-interacting protein. We demonstrated that ZNF70 interacts with ZFP64 and activates HES1 transcription by binding to the HES1 promoter. In addition, HES1 gene expression is increased in ILDR2-knockdown HepG2 cells, in which ZNF70 is translocated from the cytoplasm to the nucleus, suggesting that ZNF70 migration to the nucleus after dissociating from the ILDR2-ZNF70 complex activates HES1 transcription. These results support a novel link between ILDR2 and HES1 gene expression and suggest that ILDR2 is involved in a novel pathway in hepatic steatosis.
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. Electronic address: kwatanabe@jichi.ac.jp.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
authors.forename: Supichaya
authors.initials: S
authors.lastname: Boonvisut
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Millings
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Fischer
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.affiliation: Naomi Berrie Diabetes Center, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Iwamoto
mesh_terms: D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1 / Q000737:chemistry / Q000378:metabolism*; D016335:Zinc Fingers / Q000502:physiology*
chemical_list: C586074:ILDR2 protein, mouse; D008565:Membrane Proteins; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human
keywords: HES1 gene expression; ILDR2-Interacting protein; Kruppel C2H2-type zinc-finger protein