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A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin

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dc.contributor.author Reiling, Jan H.
dc.contributor.author Clish, Clary
dc.contributor.author Carette, Jan E.
dc.contributor.author Varadarajan, Malini
dc.contributor.author Brummelkamp, Thijn R.
dc.contributor.author Sabatini, David M.
dc.date.accessioned 2012-02-01T20:47:46Z
dc.date.available 2012-02-01T20:47:46Z
dc.date.issued 2011-06
dc.date.submitted 2010-12
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490
dc.identifier.uri http://hdl.handle.net/1721.1/69001
dc.description.abstract Tunicamycin (TM) inhibits eukaryotic asparagine-linked glycosylation, protein palmitoylation, ganglioside production, proteoglycan synthesis, 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, and cell wall biosynthesis in bacteria. Treatment of cells with TM elicits endoplasmic reticulum stress and activates the unfolded protein response. Although widely used in laboratory settings for many years, it is unknown how TM enters cells. Here, we identify in an unbiased genetic screen a transporter of the major facilitator superfamily, major facilitator domain containing 2A (MFSD2A), as a critical mediator of TM toxicity. Cells without MFSD2A are TM-resistant, whereas MFSD2A-overexpressing cells are hypersensitive. Hypersensitivity is associated with increased cellular TM uptake concomitant with an enhanced endoplasmic reticulum stress response. Furthermore, MFSD2A mutant analysis reveals an important function of the C terminus for correct intracellular localization and protein stability, and it identifies transmembrane helical amino acid residues essential for mediating TM sensitivity. Overall, our data uncover a critical role for MFSD2A by acting as a putative TM transporter at the plasma membrane. en_US
dc.description.sponsorship Human Frontier Science Program (Strasbourg, France) en_US
dc.description.sponsorship United States. National Institutes of Health (Grant R21 HG004938-01) en_US
dc.description.sponsorship United States. National Institutes of Health (Grant CA103866) en_US
dc.description.sponsorship United States. National Institutes of Health (Grant CA129105) en_US
dc.language.iso en_US
dc.publisher Proceedings of the National Academy of Sciences (PNAS) en_US
dc.relation.isversionof http://dx.doi.org/10.1073/pnas.1018098108 en_US
dc.rights Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. en_US
dc.source PNAS en_US
dc.title A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin en_US
dc.type Article en_US
dc.identifier.citation Reiling, J. H. et al. “From the Cover: Feature Article: A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin.” Proceedings of the National Academy of Sciences 108.29 (2011): 11756-11765. Web. 1 Feb. 2012. en_US
dc.contributor.department Howard Hughes Medical Institute en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Biology en_US
dc.contributor.department David H. Koch Institute for Integrative Cancer Research at MIT en_US
dc.contributor.department Broad Institute of MIT and Harvard en_US
dc.contributor.department Whitehead Institute for Biomedical Research en_US
dc.contributor.approver Sabatini, David
dc.contributor.mitauthor Reiling, Jan H.
dc.contributor.mitauthor Clish, Clary
dc.contributor.mitauthor Carette, Jan E.
dc.contributor.mitauthor Varadarajan, Malini
dc.contributor.mitauthor Brummelkamp, Thijn R.
dc.contributor.mitauthor Sabatini, David M.
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dc.identifier.mitlicense PUBLISHER_POLICY en_US
dc.eprint.version Final published version en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Reiling, J. H.; Clish, C. B.; Carette, J. E.; Varadarajan, M.; Brummelkamp, T. R.; Sabatini, D. M. en


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