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A complex containing lysine-acetylated actin inhibits the formin INF2
Mu A1, Tak Shun Fung1, Arminja N Kettenbach1
1Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Nature Cell Biology
|April 10, 2019
Summary
Researchers discovered a new inhibitor for Inverted formin 2 (INF2), a protein linked to kidney and nerve diseases. This inhibitor is a complex of lysine-acetylated actin (KAc-actin) and cyclase-associated protein (CAP), revealing a novel regulation mechanism.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Inverted formin 2 (INF2) is a key actin assembly factor.
- Mutations in INF2 cause focal segmental glomerulosclerosis and Charcot-Marie-Tooth disease.
- INF2's autoinhibition is not observed in purified protein, suggesting cellular regulation.
Purpose of the Study:
- To identify cellular inhibitors of INF2.
- To elucidate the mechanism of INF2 regulation.
- To understand how INF2 mutations lead to disease.
Main Methods:
- Purification of INF2 inhibitor from mouse brain.
- Identification of the inhibitor complex.
- Biochemical assays to test inhibition and activation.
- Analysis of disease-associated INF2 mutants.
Main Results:
- A complex of lysine-acetylated actin (KAc-actin) and cyclase-associated protein (CAP) was identified as an INF2 inhibitor.
- Inhibition is mediated by the INF2 diaphanous inhibitory domain (DID).
- Histone deacetylase 6 (HDAC6) regulates INF2 activity via this complex.
- Disease mutants show reduced binding to CAP-KAc-actin.
Conclusions:
- KAc-actin and CAP form a novel regulatory complex that inhibits INF2.
- HDAC6 plays a critical role in activating INF2.
- Reduced inhibition by CAP-KAc-actin due to mutations likely causes INF2-related diseases.
- This study reveals a new mechanism of 'facilitated autoinhibition' for actin assembly factors.
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