AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9.

Silvia Vergarajauregui,Felix B Engel,Ingo Thievessen,Florian Billing,Tilman Esser,George Schett,Maria Sharkova,Robert Becker,Michael S Kapiloff,Jana Petzold,Ulrike Steffen

doi:10.7554/elife.61669

Silvia Vergarajauregui, Felix B Engel + Show 9 more

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https://doi.org/10.7554/elife.61669

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Abstract

The switch from centrosomal microtubule-organizing centers (MTOCs) to non-centrosomal MTOCs during differentiation is poorly understood. Here, we identify AKAP6 as key component of the nuclear envelope MTOC. In rat cardiomyocytes, AKAP6 anchors centrosomal proteins to the nuclear envelope through its spectrin repeats, acting as an adaptor between nesprin-1α and Pcnt or AKAP9. In addition, AKAP6 and AKAP9 form a protein platform tethering the Golgi to the nucleus. Both Golgi and nuclear envelope exhibit MTOC activity utilizing either AKAP9, or Pcnt-AKAP9, respectively. AKAP6 is also required for formation and activity of the nuclear envelope MTOC in human osteoclasts. Moreover, ectopic expression of AKAP6 in epithelial cells is sufficient to recruit endogenous centrosomal proteins. Finally, AKAP6 is required for cardiomyocyte hypertrophy and osteoclast bone resorption activity. Collectively, we decipher the MTOC at the nuclear envelope as a bi-layered structure generating two pools of microtubules with AKAP6 as a key organizer.

Highlights

Microtubule organization plays a crucial role in cell differentiation by regulating diverse cellular processes such as cell polarization, migration, mechanotransduction, organelle positioning, and intracellular transport (Tillery et al, 2018)
AKAP6 expression is associated with Non-centrosomal MTOCs (ncMTOCs) formation in rat cardiomyocytes
To assess whether AKAP6 expression is associated with the establishment of the ncMTOC at the nuclear envelope, we analyzed the expression levels of Akap6 throughout late embryonic and early postnatal rat cardiac development when cardiomyocytes reorganize their microtubule-organizing centers (MTOCs)

Summary

Introduction

Microtubule organization plays a crucial role in cell differentiation by regulating diverse cellular processes such as cell polarization, migration, mechanotransduction, organelle positioning, and intracellular transport (Tillery et al, 2018). Upon differentiation, many cell types organize their microtubules at non-centrosomal sites. Non-centrosomal MTOCs (ncMTOCs) are, for example, found in axons and dendrites of neurons (Baas et al, 1988; SanchezHuertas et al, 2016), around the nuclear envelope of striated muscle cells (Becker et al, 2020; Tassin et al, 1985a) and osteoclasts (Mulari et al, 2003), as well as at the apical surface and the Golgi of epithelial cells (Bacallao et al, 1989; Chabin-Brion et al, 2001). Non-centrosomal microtubule organization is a hallmark of many differentiated cell types, the mechanisms regulating the switch from centrosomal MTOC to ncMTOC as well as the molecular composition and regulation of ncMTOCs are just beginning to be elucidated

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