A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin

Hiroshi Moritake, Megumi Obara, Yusuke Saito, Ayako Kashimada, Masatoshi Takagi, Megumi Funakoshi-Tago, Tomofusa Fukuyama, Mikio Yoshioka, Akira Inoue, Hiroyuki Komatsu, Hideki Nishitoh, Hiroaki Kataoka, Hiroyuki Nunoi

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)88-97
Number of pages10
JournalHuman Cell
Volume30
Issue number2
DOIs
Publication statusPublished - 2017 Apr 1

Keywords

  • DDIT3
  • GRP78
  • Mfsd2a
  • Tunicamycin
  • Unfolded protein response

ASJC Scopus subject areas

  • Cell Biology
  • Cancer Research

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  • Cite this

    Moritake, H., Obara, M., Saito, Y., Kashimada, A., Takagi, M., Funakoshi-Tago, M., Fukuyama, T., Yoshioka, M., Inoue, A., Komatsu, H., Nishitoh, H., Kataoka, H., & Nunoi, H. (2017). A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin. Human Cell, 30(2), 88-97. https://doi.org/10.1007/s13577-016-0153-7