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DYRK1B regulates Hedgehog-induced microtubule acetylation

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Abstract

The posttranslational modification (PTM) of tubulin subunits is important for the physiological functions of the microtubule (MT) cytoskeleton. Although major advances have been made in the identification of enzymes carrying out MT-PTMs, little knowledge is available on how intercellular signaling molecules and their associated pathways regulate MT-PTM-dependent processes inside signal-receiving cells. Here we show that Hedgehog (Hh) signaling, a paradigmatic intercellular signaling system, affects the MT acetylation state in mammalian cells. Mechanistically, Hh pathway activity increases the levels of the MT-associated DYRK1B kinase, resulting in the inhibition of GSK3β through phosphorylation of Serine 9 and the subsequent suppression of HDAC6 enzyme activity. Since HDAC6 represents a major tubulin deacetylase, its inhibition increases the levels of acetylated MTs. Through the activation of DYRK1B, Hh signaling facilitates MT-dependent processes such as intracellular mitochondrial transport, mesenchymal cell polarization or directed cell migration. Taken together, we provide evidence that intercellular communication through Hh signals can regulate the MT cytoskeleton and contribute to MT-dependent processes by affecting the level of tubulin acetylation.

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Abbreviations

DYRK1B:

Dual specificity-regulated kinase 1B (a.k.a. MIRK)

Hh:

Hedgehog

SHH:

Sonic Hedgehog

GLI1:

Glioma-associated oncogene 1

GSK3β:

Glycogen synthase kinase 3 beta

HDAC6:

Histone deacetylase 6

MT:

Microtubule

AcTub:

Acetylated α-tubulin

SAG:

Smoothened agonist

SANT:

Smoothened antagonist

MTOC:

Microtubule (MT) organizing center

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Acknowledgements

This work was supported by grants obtained from the German Research Society (DFG-KFO325 and DFG-LA2829/9-1), the Behring-Röntgen Foundation and the University Hospital Giessen-Marburg (UKGM).

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Authors and Affiliations

  1. Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor- and Immune Biology (ZTI), Philipps University, Hans-Meerwein-Str. 3, 35043, Marburg, Germany

    Rajeev Singh, Philipp Simon Holz, Anna Hupfer, Wolfgang Meissner, Rolf Müller & Matthias Lauth

  2. Imaging Core Facility, Center for Tumor- and Immune Biology (ZTI), Philipps University, Hans-Meerwein-Str. 3, 35043, Marburg, Germany

    Katrin Roth

  3. Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps University, Marburg, Germany

    Malte Buchholz & Thomas M. Gress

  4. Institute of Cytobiology and Cytopathology, Philipps University, Robert Koch Str. 6, 35037, Marburg, Germany

    Hans-Peter Elsässer & Ralf Jacob

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  1. Rajeev Singh
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Singh, R., Holz, P.S., Roth, K. et al. DYRK1B regulates Hedgehog-induced microtubule acetylation. Cell. Mol. Life Sci. 76, 193–207 (2019). https://doi.org/10.1007/s00018-018-2942-5

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