MTCH2 is a mitochondrial outer membrane protein insertase

  • Science. 2022 Oct 21;378(6617):317-322. doi: 10.1126/science.add1856.
Alina Guna  #  1 ,  Taylor A Stevens  #  2 ,  Alison J Inglis  #  2 ,  Joseph M Replogle  1  3  4  5 ,  Theodore K Esantsi  1  5 ,  Gayathri Muthukumar  1  6 ,  Kelly C L Shaffer  2 ,  Maxine L Wang  1  2  6 ,  Angela N Pogson  1  5 ,  Jeff J Jones  2 ,  Brett Lomenick  2 ,  Tsui-Fen Chou  2 ,  Jonathan S Weissman  1  5  6  7 ,  Rebecca M Voorhees  2
Affiliations
  • 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.
  • # Contributed equally.
PMID: 36264797 DOI: 10.1126/science.add1856
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.