MTCH2 is a mitochondrial outer membrane protein insertase-Reference-Cited by-同舟云学术

MTCH2 is a mitochondrial outer membrane protein insertase

Published:2022-10-21 Issue:6617 Volume:378 Page:317-322
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Guna Alina¹^ORCID,Stevens Taylor A.²^ORCID,Inglis Alison J.²^ORCID,Replogle Joseph M.¹³⁴⁵^ORCID,Esantsi Theodore K.¹⁵,Muthukumar Gayathri¹⁶,Shaffer Kelly C. L.²,Wang Maxine L.¹²⁶^ORCID,Pogson Angela N.¹⁵^ORCID,Jones Jeff J.²^ORCID,Lomenick Brett²^ORCID,Chou Tsui-Fen²^ORCID,Weissman Jonathan S.¹⁵⁶⁷^ORCID,Voorhees Rebecca M.²^ORCID

Affiliation:

1. Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

2. Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Avenue, Pasadena, CA 91125, USA.

3. Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA.

4. Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.

5. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

6. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

7. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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