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MTCH2 is a mitochondrial outer membrane protein insertase

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. . (Unpublished)

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In the mitochondrial outer membrane, tail-anchored (TA) proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPRi screens, we identify factors involved in mitochondrial TA biogenesis in human cells. We show that MTCH2, and its paralog MTCH1, are required for insertion of biophysically diverse mitochondrial TAs, but not outer membrane β-barrel proteins. In a reconstituted system, purified MTCH2 is sufficient to mediate insertion into proteoliposomes. Functional and mutational studies reveal that MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for outer membrane protein biogenesis, controlling mislocalization of TAs into the endoplasmic reticulum and 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.One-Sentence SummaryMTCH2 is both necessary and sufficient for insertion of diverse α-helical proteins into the mitochondrial outer membrane, and is the defining member of a family of insertases that have co-opted the SLC25 transporter fold.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemJournal Article
Guna, Alina0000-0003-0757-1255
Stevens, Taylor A.0000-0002-6232-5316
Inglis, Alison J.0000-0002-9008-8565
Replogle, Joseph M.0000-0003-1832-919X
Shaffer, Kelly C.L.0000-0002-6212-1428
Wang, Maxine L.0000-0002-5285-1857
Pogson, Angela N.0000-0002-6927-2456
Jones, Jeff J.0000-0002-7142-2222
Lomenick, Brett0000-0002-5023-9998
Chou, Tsui-Fen0000-0003-2410-2186
Weissman, Jonathan S.0000-0003-2445-670X
Voorhees, Rebecca M.0000-0003-1640-2293
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. We thank T. Pleiner and Z. Levine for careful reading and input on the manuscript. We thank: the Whitehead Institute Flow Cytometry Core and Kathy 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 the Ting-Yu Wang and the Proteome Exploration Laboratory at Caltech for support for mass spectrometry. Research reported in this publication was supported by: Howard Hughes Medical Institute (JSW), Human Frontier Science Program 2019L/LT000858 (AG), the Heritage Medical Research Institute (RMV), and the Larry L. Hillblom Foundation (AJI). Competing Interest Statement. JMR consults for Maze Therapeutics and is a consultant for and equity holder in Waypoint Bio. JSW declares outside interest in 5 AM Venture, Amgen, Chroma Medicine, KSQ Therapeutics, Maze Therapeutics, Tenaya Therapeutics, Tessera Therapeutics and Third Rock Ventures. RMV is a consultant and equity holder in Gate Bioscience.
Group:Heritage Medical Research Institute, Tianqiao and Chrissy Chen Institute for Neuroscience
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Human Frontier Science Program2019L/LT000858
Heritage Medical Research InstituteUNSPECIFIED
Larry L. Hillblom FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20230228-37943000.2
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:119571
Deposited By: George Porter
Deposited On:28 Feb 2023 19:52
Last Modified:11 Apr 2023 15:33

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