title: F-actin dismantling through a redox-driven synergy between Mical and cofilin.
abstract: Numerous cellular functions depend on actin filament (F-actin) disassembly. The best-characterized disassembly proteins, the ADF (actin-depolymerizing factor)/cofilins (encoded by the twinstar gene in Drosophila), sever filaments and recycle monomers to promote actin assembly. Cofilin is also a relatively weak actin disassembler, posing questions about mechanisms of cellular F-actin destabilization. Here we uncover a key link to targeted F-actin disassembly by finding that F-actin is efficiently dismantled through a post-translational-mediated synergism between cofilin and the actin-oxidizing enzyme Mical. We find that Mical-mediated oxidation of actin improves cofilin binding to filaments, where their combined effect dramatically accelerates F-actin disassembly compared with either effector alone. This synergism is also necessary and sufficient for F-actin disassembly in vivo, magnifying the effects of both Mical and cofilin on cellular remodelling, axon guidance and Semaphorin-Plexin repulsion. Mical and cofilin, therefore, form a redox-dependent synergistic pair that promotes F-actin instability by rapidly dismantling F-actin and generating post-translationally modified actin that has altered assembly properties.
authors.affiliation: Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Grintsevich
authors.affiliation: Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Hunkar Gizem
authors.initials: HG
authors.lastname: Yesilyurt
authors.affiliation: Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Rich
authors.affiliation: Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ruei-Jiun
authors.initials: RJ
authors.lastname: Hung
authors.affiliation: Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Terman
authors.affiliation: Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California 90095, USA.|Molecular Biology Institute, University of California-Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Reisler
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D051338:Cofilin 1 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051345:Destrin / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000235:genetics; D011817:Rabbits
chemical_list: D000199:Actins; D051338:Cofilin 1; D004268:DNA-Binding Proteins; D051345:Destrin; C496247:MICAL protein, Drosophila