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Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.

Ran J, Yang Y, Li D, Liu M, Zhou J - Sci Rep (2015)

Bottom Line: Ciliary dysfunction is associated with a variety of diseases known as ciliopathies.Overexpression of HDAC6 decreases the levels of acetylated α-tubulin and cortactin without affecting the expression or localization of known ciliary regulators.These findings provide mechanistic insight into the ciliary role of HDAC6 and underscore the importance of reversible acetylation in regulating ciliary homeostasis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.

ABSTRACT
Cilia play important roles in sensing extracellular signals and directing fluid flow. Ciliary dysfunction is associated with a variety of diseases known as ciliopathies. Histone deacetylase 6 (HDAC6) has recently emerged as a major driver of ciliary disassembly, but little is known about the downstream players. Here we provide the first evidence that HDAC6-mediated deacetylation of α-tubulin and cortactin is critical for its induction of ciliary disassembly. HDAC6 is localized in the cytoplasm and enriched at the centrosome and basal body. Overexpression of HDAC6 decreases the levels of acetylated α-tubulin and cortactin without affecting the expression or localization of known ciliary regulators. We also find that overexpression of α-tubulin or cortactin or their acetylation-deficient mutants enhances the ability of HDAC6 to induce ciliary disassembly. In addition, acetylation-mimicking mutants of α-tubulin and cortactin counteract HDAC6-induced ciliary disassembly. Furthermore, HDAC6 stimulates actin polymerization, and inhibition of actin polymerization abolishes the activity of HDAC6 to trigger ciliary disassembly. These findings provide mechanistic insight into the ciliary role of HDAC6 and underscore the importance of reversible acetylation in regulating ciliary homeostasis.

No MeSH data available.


Molecular model for the role of HDAC6 in ciliary disassembly.HDAC6-mediated ciliary disassembly is dependent on the deacetylation of both α-tubulin and cortactin; deacetylation of α-tubulin reduces the stability of axoneme microtubules, whereas deacetylation of cortactin promotes its interaction with F-actin and accelerates actin polymerization, which in turn leads to ciliary resorption.
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f10: Molecular model for the role of HDAC6 in ciliary disassembly.HDAC6-mediated ciliary disassembly is dependent on the deacetylation of both α-tubulin and cortactin; deacetylation of α-tubulin reduces the stability of axoneme microtubules, whereas deacetylation of cortactin promotes its interaction with F-actin and accelerates actin polymerization, which in turn leads to ciliary resorption.

Mentions: HDAC6 is a unique member of the HDAC family that mainly deacetylates non-histone substrates. A variety of proteins have been identified as HDAC6 substrates, including α-tubulin, cortactin, Hsp90, peroxiredoxin, and Tat18192021222324. By modulating the acetylation of these proteins, HDAC6 plays an important role in diverse cellular processes, such as cell motility and signaling18192021222324. Accumulating evidence has shown that HDAC6 is critically involved in ciliary disassembly567891011121314151617. However, the molecular mechanism of how HDAC6 functions in the control of cilia remains elusive, and it is unclear whether any known substrate of HDAC6 mediates its ciliary function. In this study, by a combination of multiple approaches, we demonstrate for the first time that deaetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly; deacetylation of α-tubulin by HDAC6 reduces the stability of axoneme microtubules, whereas deacetylation of cortactin by HDAC6 promotes the interaction of cortactin with F-actin and accelerates actin polymerization, which in turn leads to ciliary resorption (Fig. 10).


Deacetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly.

Ran J, Yang Y, Li D, Liu M, Zhou J - Sci Rep (2015)

Molecular model for the role of HDAC6 in ciliary disassembly.HDAC6-mediated ciliary disassembly is dependent on the deacetylation of both α-tubulin and cortactin; deacetylation of α-tubulin reduces the stability of axoneme microtubules, whereas deacetylation of cortactin promotes its interaction with F-actin and accelerates actin polymerization, which in turn leads to ciliary resorption.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526867&req=5

f10: Molecular model for the role of HDAC6 in ciliary disassembly.HDAC6-mediated ciliary disassembly is dependent on the deacetylation of both α-tubulin and cortactin; deacetylation of α-tubulin reduces the stability of axoneme microtubules, whereas deacetylation of cortactin promotes its interaction with F-actin and accelerates actin polymerization, which in turn leads to ciliary resorption.
Mentions: HDAC6 is a unique member of the HDAC family that mainly deacetylates non-histone substrates. A variety of proteins have been identified as HDAC6 substrates, including α-tubulin, cortactin, Hsp90, peroxiredoxin, and Tat18192021222324. By modulating the acetylation of these proteins, HDAC6 plays an important role in diverse cellular processes, such as cell motility and signaling18192021222324. Accumulating evidence has shown that HDAC6 is critically involved in ciliary disassembly567891011121314151617. However, the molecular mechanism of how HDAC6 functions in the control of cilia remains elusive, and it is unclear whether any known substrate of HDAC6 mediates its ciliary function. In this study, by a combination of multiple approaches, we demonstrate for the first time that deaetylation of α-tubulin and cortactin is required for HDAC6 to trigger ciliary disassembly; deacetylation of α-tubulin by HDAC6 reduces the stability of axoneme microtubules, whereas deacetylation of cortactin by HDAC6 promotes the interaction of cortactin with F-actin and accelerates actin polymerization, which in turn leads to ciliary resorption (Fig. 10).

Bottom Line: Ciliary dysfunction is associated with a variety of diseases known as ciliopathies.Overexpression of HDAC6 decreases the levels of acetylated α-tubulin and cortactin without affecting the expression or localization of known ciliary regulators.These findings provide mechanistic insight into the ciliary role of HDAC6 and underscore the importance of reversible acetylation in regulating ciliary homeostasis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.

ABSTRACT
Cilia play important roles in sensing extracellular signals and directing fluid flow. Ciliary dysfunction is associated with a variety of diseases known as ciliopathies. Histone deacetylase 6 (HDAC6) has recently emerged as a major driver of ciliary disassembly, but little is known about the downstream players. Here we provide the first evidence that HDAC6-mediated deacetylation of α-tubulin and cortactin is critical for its induction of ciliary disassembly. HDAC6 is localized in the cytoplasm and enriched at the centrosome and basal body. Overexpression of HDAC6 decreases the levels of acetylated α-tubulin and cortactin without affecting the expression or localization of known ciliary regulators. We also find that overexpression of α-tubulin or cortactin or their acetylation-deficient mutants enhances the ability of HDAC6 to induce ciliary disassembly. In addition, acetylation-mimicking mutants of α-tubulin and cortactin counteract HDAC6-induced ciliary disassembly. Furthermore, HDAC6 stimulates actin polymerization, and inhibition of actin polymerization abolishes the activity of HDAC6 to trigger ciliary disassembly. These findings provide mechanistic insight into the ciliary role of HDAC6 and underscore the importance of reversible acetylation in regulating ciliary homeostasis.

No MeSH data available.