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A complex containing lysine-acetylated actin inhibits the formin INF2

INF2 is a member of the formin family of actin assembly factors. Dominant mis-sense mutations in INF2 link to two diseases: focal segmental glomerulosclerosis (FSGS), a kidney disease; and Charcot-Marie-Tooth disease (CMTD), a neuropathy. All disease mutations map to the autoinhibitory Diaphanous In...

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Autores principales: Mu, A, Fung, Tak Shun, Kettenbach, Arminja N., Chakrabarti, Rajarshi, Higgs, Henry N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501848/
https://www.ncbi.nlm.nih.gov/pubmed/30962575
http://dx.doi.org/10.1038/s41556-019-0307-4
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author Mu, A
Fung, Tak Shun
Kettenbach, Arminja N.
Chakrabarti, Rajarshi
Higgs, Henry N.
author_facet Mu, A
Fung, Tak Shun
Kettenbach, Arminja N.
Chakrabarti, Rajarshi
Higgs, Henry N.
author_sort Mu, A
collection PubMed
description INF2 is a member of the formin family of actin assembly factors. Dominant mis-sense mutations in INF2 link to two diseases: focal segmental glomerulosclerosis (FSGS), a kidney disease; and Charcot-Marie-Tooth disease (CMTD), a neuropathy. All disease mutations map to the autoinhibitory Diaphanous Inhibitory Domain (DID). Curiously, purified INF2 is not autoinhibited, suggesting the existence of additional cellular inhibitors. We purified an INF2 inhibitor from mouse brain, and identified it as a complex between lysine-acetylated actin (KAc-actin) and cyclase-associated protein (CAP). Inhibition of INF2 by CAP/KAc-actin requires INF2 DID. Treatment of CAP/KAc-actin with histone deacetylase 6 (HDAC6) releases INF2 inhibition, while HDAC6 inhibitors block cellular INF2 activation. INF2 disease mutants are poorly inhibited by CAP/KAc-actin, suggesting that FSGS and CMTD result from reduced CAP/KAc-actin binding. These findings reveal a role for lysine-acetylated actin in the regulation of an actin assembly factor by a mechanism which we call facilitated auto-inhibition.
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spelling pubmed-65018482019-10-08 A complex containing lysine-acetylated actin inhibits the formin INF2 Mu, A Fung, Tak Shun Kettenbach, Arminja N. Chakrabarti, Rajarshi Higgs, Henry N. Nat Cell Biol Article INF2 is a member of the formin family of actin assembly factors. Dominant mis-sense mutations in INF2 link to two diseases: focal segmental glomerulosclerosis (FSGS), a kidney disease; and Charcot-Marie-Tooth disease (CMTD), a neuropathy. All disease mutations map to the autoinhibitory Diaphanous Inhibitory Domain (DID). Curiously, purified INF2 is not autoinhibited, suggesting the existence of additional cellular inhibitors. We purified an INF2 inhibitor from mouse brain, and identified it as a complex between lysine-acetylated actin (KAc-actin) and cyclase-associated protein (CAP). Inhibition of INF2 by CAP/KAc-actin requires INF2 DID. Treatment of CAP/KAc-actin with histone deacetylase 6 (HDAC6) releases INF2 inhibition, while HDAC6 inhibitors block cellular INF2 activation. INF2 disease mutants are poorly inhibited by CAP/KAc-actin, suggesting that FSGS and CMTD result from reduced CAP/KAc-actin binding. These findings reveal a role for lysine-acetylated actin in the regulation of an actin assembly factor by a mechanism which we call facilitated auto-inhibition. 2019-04-08 2019-05 /pmc/articles/PMC6501848/ /pubmed/30962575 http://dx.doi.org/10.1038/s41556-019-0307-4 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Mu, A
Fung, Tak Shun
Kettenbach, Arminja N.
Chakrabarti, Rajarshi
Higgs, Henry N.
A complex containing lysine-acetylated actin inhibits the formin INF2
title A complex containing lysine-acetylated actin inhibits the formin INF2
title_full A complex containing lysine-acetylated actin inhibits the formin INF2
title_fullStr A complex containing lysine-acetylated actin inhibits the formin INF2
title_full_unstemmed A complex containing lysine-acetylated actin inhibits the formin INF2
title_short A complex containing lysine-acetylated actin inhibits the formin INF2
title_sort complex containing lysine-acetylated actin inhibits the formin inf2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501848/
https://www.ncbi.nlm.nih.gov/pubmed/30962575
http://dx.doi.org/10.1038/s41556-019-0307-4
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