A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin.
| Title: | 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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| Authors: | Reiling JH; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; Clish CB; Carette JE; Varadarajan M; Brummelkamp TR; Sabatini DM |
| Source: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2011 Jul 19; Vol. 108 (29), pp. 11756-65. Date of Electronic Publication: 2011 Jun 15. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : National Academy of Sciences |
| MeSH Terms: | Endoplasmic Reticulum/*metabolism ; Membrane Transport Proteins/*metabolism ; Protein Folding/*drug effects ; Signal Transduction/*physiology ; Tumor Suppressor Proteins/*metabolism ; Tunicamycin/*pharmacology; Glycosylation/drug effects ; Tumor Suppressor Proteins/genetics ; Blotting, Western ; Cell Line ; Cell Survival ; Humans ; Immunoprecipitation ; Microscopy, Confocal ; Symporters |
| 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. |
| Comments: | Comment in: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11731-2. doi: 10.1073/pnas.1109035108.. (PMID: 21734150) |
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| Grant Information: | R01 CA103866 United States CA NCI NIH HHS; CA103866 United States CA NCI NIH HHS; CA129105 United States CA NCI NIH HHS; R01 CA129105 United States CA NCI NIH HHS; R21 HG004938-01 United States HG NHGRI NIH HHS; United States HHMI Howard Hughes Medical Institute; R21 HG004938 United States HG NHGRI NIH HHS |
| Substance Nomenclature: | 0 (MFSD2A protein, human); 0 (Membrane Transport Proteins); 0 (Symporters); 0 (Tumor Suppressor Proteins); 11089-65-9 (Tunicamycin) |
| Entry Date(s): | Date Created: 20110617 Date Completed: 20111003 Latest Revision: 20211020 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC3141996 |
| DOI: | 10.1073/pnas.1018098108 |
| PMID: | 21677192 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't