title: A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin.
abstract: Major facilitator superfamily domain containing 2a (Mfsd2a) is a member of the major facilitator superfamily. Mfsd2a functions as a transporter for docosahexaenoic acid and also plays a role in the unfolded protein response (UPR) upon tunicamycin (TM) exposure. UPR is involved in the pathogenesis of various human diseases. TM and thapsigargin are representative experimental reagents that induce UPR. To elucidate the detailed function of Mfsd2a in UPR in vivo, we generated Mfsd2a-deficient mice and investigated the role of Mfsd2a during UPR induced by TM or thapsigargin. Phenotypically, Mfsd2a-deficient mice were small and short-lived. No gross anatomical abnormalities in Mfsd2a-deficient mice compared with the wild-type mice were exhibited. Embryonic fibroblasts derived from Mfsd2a-null mice failed to show induction of GRP78 and DDIT3 expressions upon TM exposure but not upon Tg exposure. This phenomenon could not be overcome despite the exposure under high TM concentration. Reconstitution of Mfsd2a in Mfsd2a-null MEF showed hypersensitivity to TM. Furthermore, we examined the physiological role of Mfsd2a against TM using an in vivo mouse model. DDIT3 induction by TM was drastically attenuated in both the liver and brain of Mfsd2a-deficient mice. These results reveal that Mfsd2a plays a critical role in UPR upon TM exposure.
authors.affiliation: Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan. hiroshi_moritake@med.miyazaki-u.ac.jp.|Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA. hiroshi_moritake@med.miyazaki-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritake
authors.affiliation: Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Obara
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kashimada
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA.|Department of Hygiene Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA.|Division of Cellular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomofusa
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA.|Department of Pediatrics, KKR Sapporo Medical Center, Sapporo, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Yoshioka
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Center for Medical Education, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nunoi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D058767:Protein Unfolding / Q000187:drug effects*; D027981:Symporters; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology*
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D026901:Membrane Transport Proteins; C534136:Mfsd2a protein, mouse; D027981:Symporters; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D019284:Thapsigargin
keywords: DDIT3; GRP78; Mfsd2a; Tunicamycin; Unfolded protein response