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

doi:10.1007/s13577-016-0153-7

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

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

6 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 language	English
Pages (from-to)	88-97
Number of pages	10
Journal	Human Cell
Volume	30
Issue number	2
DOIs	https://doi.org/10.1007/s13577-016-0153-7
Publication status	Published - 2017 Apr 1

Keywords

DDIT3
GRP78
Mfsd2a
Tunicamycin
Unfolded protein response

ASJC Scopus subject areas

Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s13577-016-0153-7

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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.",

keywords = "DDIT3, GRP78, Mfsd2a, Tunicamycin, Unfolded protein response",

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

note = "Funding Information: This work was partially supported by the Japanese Ministry of Education. We thank Ms. Megumi Hatanaka and Kanako Sakamoto for providing technical support in our experiments. Publisher Copyright: {\textcopyright} 2016, Japan Human Cell Society and Springer Japan.",

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doi = "10.1007/s13577-016-0153-7",

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T1 - A mouse model reveals that Mfsd2a is critical for unfolded protein response upon exposure to tunicamycin

AU - Moritake, Hiroshi

AU - Obara, Megumi

AU - Saito, Yusuke

AU - Kashimada, Ayako

AU - Takagi, Masatoshi

AU - Funakoshi-Tago, Megumi

AU - Fukuyama, Tomofusa

AU - Yoshioka, Mikio

AU - Inoue, Akira

AU - Komatsu, Hiroyuki

AU - Nishitoh, Hideki

AU - Kataoka, Hiroaki

AU - Nunoi, Hiroyuki

N1 - Funding Information: This work was partially supported by the Japanese Ministry of Education. We thank Ms. Megumi Hatanaka and Kanako Sakamoto for providing technical support in our experiments. Publisher Copyright: © 2016, Japan Human Cell Society and Springer Japan.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

KW - DDIT3

KW - GRP78

KW - Mfsd2a

KW - Tunicamycin

KW - Unfolded protein response

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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