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

Moritake, Hiroshi; Obara, Megumi; Saito, Yûsuke; Kashimada, Ayako; Takagi, Motoki; Funakoshi‐Tago, Megumi; Yoshioka, Masaharu; Inoue, Akira; Komatsu, Hiroyuki; Nishitoh, Hideki; Kataoka, Hiroaki; Nunoi, Hiroyuki

doi:10.1007/s13577-016-0153-7

Cited by 8 publications

(7 citation statements)

References 14 publications

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“…Consistent with a role in transport, Mfsd2a was shown to be localized to the plasma membrane (Reiling et al, ). The role of Mfsd2a as a tunicamycin transporter was further supported by in vivo studies as well (Moritake et al, ).…”

Section: Roles Of Mfsd2a In Physiological and Pathological Conditionsmentioning

confidence: 84%

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Ocak

Sherchan

et al. 2018

J of Neuroscience Research

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Major facilitator superfamily domain-containing protein-2a (Mfsd2a) which was considered as an orphan transporter has recently gained attention for its regulatory role in the maintenance of proper functioning of the blood-brain barrier. Besides the major role of Mfsd2a in maintaining the barrier function, increasing evidence has emerged with regard to the contributions of Mfsd2a to various biological processes such as transport, cell fusion, cell cycle, inflammation and regeneration, managing tumor growth, functioning of other organs with barrier functions or responses to injury. The purpose of this article is to review the different roles of Mfsd2a and its involvement in the physiological and pathophysiological processes primarily in the central nervous system and throughout the mammalian body under the lights of the current literature.

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Section: Roles Of Mfsd2a In Physiological and Pathological Conditionsmentioning

confidence: 84%

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Ocak

Sherchan

et al. 2018

J of Neuroscience Research

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“…2D). Given the obvious escape from inhibition of N-glycosylation, we examined expression of the lysophosphatidyl choline / docosahexaenoate transporter Mfsd2a, which is known to encode the primary plasmalemmal transport mechanism for TUN (17,18). Indeed, PCCL3 cells that had been slowly adapted to increasing doses of TUN eventually suppressed Mfsd2a mRNA expression > 500-fold ( Fig.…”

Section: Development Of a Cell Culture Model Of Chronic Continuous Ermentioning

confidence: 99%

Thyrocyte cell survival and adaptation to chronic endoplasmic reticulum stress due to misfolded thyroglobulin

Morishita

Kabil

Young

et al. 2020

Journal of Biological Chemistry

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The large secretory glycoprotein thyroglobulin is the primary translation product of thyroid follicular cells. This difficult-to-fold protein is susceptible to structural alterations that disable export of the misfolded thyroglobulin from the endoplasmic reticulum (ER), which is a known cause of congenital hypothyroidism characterized by severe chronic thyrocyte ER stress. Nevertheless, individuals with this disease commonly grow a goiter, indicating thyroid cell survival and adaptation. To model these processes, here we continuously exposed rat PCCL3 thyrocytes to tunicamycin, which causes a significant degree of ER stress that is specifically attributable to thyroglobulin misfolding. We found that, in response, PCCL3 cells down-regulate expression of the “tunicamycin transporter” (major facilitator superfamily domain containing-2A, Mfsd2a). Following CRISPR/Cas9-mediated Mfsd2a deletion, PCCL3 cells could no longer escape the chronic effects of high-dose tunicamycin, as demonstrated by persistent accumulation of unglycosylated thyroglobulin; nevertheless, these thyrocytes survived and grew. A proteomic analysis of these cells adapted to chronic ER protein misfolding revealed many hundreds of up-regulated proteins, indicating stimulation of ER chaperones, oxidoreductases, stress responses, and lipid biosynthesis pathways. Further, we noted increased phospho–AMP-kinase, suggesting up-regulated AMP-kinase activity, and decreased phospho–S6-kinase and protein translation, suggesting decreased mTOR activity. These changes are consistent with conserved cell survival/adaptation pathways. We also observed a less-differentiated thyrocyte phenotype with decreased PAX8, FOXE1, and TPO protein levels, along with decreased thyroglobulin mRNA levels. In summary, we have developed a model of thyrocyte survival and growth during chronic continuous ER stress that recapitulates features of congenital hypothyroid goiter caused by mutant thyroglobulin.

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“…[ 20 ] The major pathological manifestations of TM toxicity occur foremost in the liver through gross pathological examination. [ 12 ] However, TM@TTP and DOX@TTP–HA exhibited limited influence on liver function (Figure 6C), suggesting low in vivo hepatotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…[ 10b ] Mfsd2a is closely related to the unfolded protein response upon TM exposure. [ 12 ] It has been reported that mice treated with TM have >1000‐fold more virus in the brain after virus infection as compared to untreated mice. [ 13 ] TM did not alter the viremia profiles of these viruses nor the virus replication in the brain itself.…”

Section: Introductionmentioning

confidence: 99%

Overcoming Mfsd2a‐Mediated Low Transcytosis to Boost Nanoparticle Delivery to Brain for Chemotherapy of Brain Metastases

Miao

Chen

et al. 2021

Adv Healthcare Materials

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Microvessels of the blood–brain barrier (BBB) exclusively express the major facilitator superfamily domain‐containing protein 2a (Mfsd2a), which is the key transporter for docosahexaenoic acid uptake into the brain. Mfsd2a suppresses caveolae‐mediated transcytosis to regulate BBB transcellular permeability via controlling lipid composition of BBB endothelial cells. It is speculated that Mfsd2a can restrain BBB crossing efficiency and brain accumulation efficiency of brain‐targeting drug delivery systems, which penetrate the BBB often through the receptor‐mediated transcytosis pathway. Transcytosis across the BBB is a crucial bottleneck for targeted chemotherapy of brain metastases. To overcome this issue, a pair of priming nanoparticles (NPs) and following drug‐loaded NPs are designed. Tunicamycin‐(TM)‐loaded transcytosis‐targeting‐peptide‐(TTP)‐decorated NPs (TM@TTP) are used to boost BBB transcytosis via inhibiting Mfsd2a. Doxorubicin (DOX)‐loaded TTP and CD44‐specific hyaluronic acid (HA)‐comodified NPs (DOX@TTP–HA) are designed as following drug‐loaded NPs. The brain accumulation efficacy of following DOX@TTP–HA with priming is 4.30‐fold higher than that without priming through the enhanced transcytosis pathway rather than the tight junction opening. Effective BBB crossing and brain accumulation, selective tumor uptake, excellent antitumor efficacy, and low hepatotoxicity are achieved by TM@TTP and DOX@TTP–HA, suggesting this tactic as a significant therapeutic strategy against breast cancer brain metastases.

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

Cited by 8 publications

References 14 publications

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Thyrocyte cell survival and adaptation to chronic endoplasmic reticulum stress due to misfolded thyroglobulin

Overcoming Mfsd2a‐Mediated Low Transcytosis to Boost Nanoparticle Delivery to Brain for Chemotherapy of Brain Metastases

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