Guna, Alina and Stevens, Taylor A. and Inglis, Alison J. and Replogle, Joseph M. and Esantsi, Theodore K. and Muthukumar, Gayathri and Shaffer, Kelly C. L. and Wang, Maxine L. and Pogson, Angela N. and Jones, Jeff J. and Lomenick, Brett and Chou, Tsui-Fen and Weissman, Jonathan S. and Voorhees, Rebecca M. (2022) MTCH2 is a mitochondrial outer membrane protein insertase. Science, 378 (6617). pp. 317-322. ISSN 0036-8075. PMCID PMC9674023. doi:10.1126/science.add1856. https://resolver.caltech.edu/CaltechAUTHORS:20230228-36558000.1
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Abstract
In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction.
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| Additional Information: | © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. We thank J. Nunnari and M. Le Vasseur for sharing the mitochondrial split GFP system. We thank T. Pleiner for technical assistance and Z. Levine for careful reading and input on the manuscript. We thank the Whitehead Institute Flow Cytometry Core and K. Daniels for access to FACS machines; the Whitehead Institute Genome Technology Core for support with sequencing of screen libraries; the Caltech Flow cytometry facility; and T. Y. Wang and for support for mass spectrometry. Research reported in this publication was supported by Howard Hughes Medical Institute (J.S.W.), Human Frontier Science Program 2019L/LT000858 (A.G.), the Heritage Medical Research Institute (R.M.V.), the Larry L. Hillblom Foundation (A.J.I.), and NIH F31-NS115380 (J.M.R.). Author contributions: A.G., J.S.W., and R.M.V. conceived the study. A.G., T.A.S., A.J.I., J.M.R., J.S.W., and R.M.V. were responsible for the design, analysis, and interpretation of experiments. A.G., T.A.S., and A.J.I. performed most of the experiments in the study with help from J.M.R., T.K.E., G.M., B.L., K.C.S., M.L.W., and A.N.P. T.C., B.L., and J.J.J. advised the design, sample processing, and analysis for all mass spectrometry experiments. A.G. and R.M.V. drafted the manuscript with input from all authors. Competing interests: J.M.R. consults for Maze Therapeutics and is a consultant for and equity holder in Waypoint Bio. J.S.W. declares outside interest in 5 AM Venture, Amgen, Chroma Medicine, KSQ Therapeutics, Maze Therapeutics, Tenaya Therapeutics, Tessera Therapeutics, and Third Rock Ventures. R.M.V. is a consultant and equity holder in Gate Bioscience. | ||||||||||||||||||||||||||
| Group: | Heritage Medical Research Institute, Tianqiao and Chrissy Chen Institute for Neuroscience | ||||||||||||||||||||||||||
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| Issue or Number: | 6617 | ||||||||||||||||||||||||||
| PubMed Central ID: | PMC9674023 | ||||||||||||||||||||||||||
| DOI: | 10.1126/science.add1856 | ||||||||||||||||||||||||||
| Record Number: | CaltechAUTHORS:20230228-36558000.1 | ||||||||||||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20230228-36558000.1 | ||||||||||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||||||||||
| ID Code: | 119570 | ||||||||||||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||||||||||||
| Deposited By: | George Porter | ||||||||||||||||||||||||||
| Deposited On: | 28 Feb 2023 19:50 | ||||||||||||||||||||||||||
| Last Modified: | 11 Apr 2023 15:33 |
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