title: The endoplasmic reticulum stress transducer BBF2H7 suppresses apoptosis by activating the ATF5-MCL1 pathway in growth plate cartilage.
abstract: BBF2H7 (box B-binding factor 2 human homolog on chromosome 7) is a basic leucine zipper transmembrane transcription factor that belongs to the cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) family. This novel endoplasmic reticulum (ER) stress transducer is localized in the ER and is cleaved in its transmembrane region in response to ER stress. BBF2H7 has been shown to be expressed in proliferating chondrocytes in cartilage during the development of long bones. The target of BBF2H7 is Sec23a, one of the coat protein complex II components. Bbf2h7-deficient (Bbf2h7(-/-)) mice exhibit severe chondrodysplasia, with expansion of the rough ER in proliferating chondrocytes caused by impaired secretion of extracellular matrix (ECM) proteins. We observed a decrease in the number of proliferating chondrocytes in the cartilage of Bbf2h7(-/-) mice. TUNEL staining of the cartilage showed that apoptosis was promoted in Bbf2h7(-/-) chondrocytes. Atf5 (activating transcription factor 5), another member of the CREB/ATF family and an antiapoptotic factor, was also found to be a target of BBF2H7 in chondrocytes. ATF5 activated the transcription of Mcl1 (myeloid cell leukemia sequence 1), which belongs to the antiapoptotic B-cell leukemia/lymphoma 2 family, to suppress apoptosis. Finally, we found that the BBF2H7-ATF5-MCL1 pathway specifically suppressed ER stress-induced apoptosis in chondrocytes. Taken together, our findings indicate that BBF2H7 is activated in response to ER stress caused by synthesis of abundant ECM proteins and plays crucial roles as a bifunctional regulator to accelerate ECM protein secretion and suppress ER stress-induced apoptosis by activating the ATF5-MCL1 pathway during chondrogenesis.
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan and.
authors.forename: Soutarou
authors.initials: S
authors.lastname: Izumi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.forename: Soshi
authors.initials: S
authors.lastname: Kanemoto
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kawasaki
authors.forename: Rie
authors.initials: R
authors.lastname: Asada
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Mami
authors.initials: M
authors.lastname: Oki
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Miyagi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ochi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002356:Cartilage / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C544811:Creb3l2 protein, mouse; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C079038:Sec23a protein, mouse; D033921:Vesicular Transport Proteins