Author:
Guna Alina,Stevens Taylor A.,Inglis Alison J.,Replogle Joseph M.,Esantsi Theodore K.,Muthukumar Gayathri,Shaffer Kelly C.L.,Wang Maxine L.,Pogson Angela N.,Jones Jeff J.,Lomenick Brett,Chou Tsui-Fen,Weissman Jonathan S.,Voorhees Rebecca M.
Abstract
AbstractIn 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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