Essential role of AKAP6 in NE-MTOC formation and LINC complex function in cardiomyocytes

Microtubule (MT) organization plays a crucial role in cell differentiation, governing various cellular processes like cell polarization, mechanotransduction, organelle positioning, and intracellular transport. In proliferating animal cells, the centrosome serves as the primary MT-organizing center (MTOC). However, in mammalian cardiomyocytes (CMs), the centrosomal MTOC is disassembled and a dominant MTOC is established at the nuclear envelope (NE). We have identified AKAP6 as a key component of the NE-MTOC in CMs. Through its spectrin repeats, AKAP6 anchors MTOC proteins to the NE, acting as an essential adaptor between the LINC protein nesprin-1α and the MT nucleators Pcnt or AKAP9.

However, the specific functions of the MTs generated by the NE-MTOC in striated muscle cells are unclear. In addition, it remains unclear how the NE-MTOC contributes to/regulates the overall distribution and function of the MT network and whether perinuclear MTs, via AKAP6-nesprin-1α interact with the LINC complex coupling the MT cytoskeleton with the nucleoskeleton to regulate nuclear mechanics.

Recently, a push-pull balance between MTs and intermediate filaments at the nucleus has been proposed, where desmin-nesprin-3 tethering of the nucleus protects it from MT-dependent infolding, collapse, and DNA damage. Our preliminary data show that depletion of AKAP6 rescues the nuclear infolding phenotype in desmin knockdown CMs. Thus AKAP6/nesprin-1α might contribute to the translation of mechanical cues into biochemical signals through the LINC complex.

To elucidate the role of the NE-MTOC, we have generated a cardiac-specific AKAP6 knockout mouse; as global AKAP6 deletion results in perinatal lethality, similar to nesprin-1. The specific deletion of AKAP6 in CMs leads to a prominent change in nuclear positioning and morphology.

Moreover, we have discovered new domains in AKAP6 and nesprin-1α that regulate their interaction and NE-MTOC formation. Our findings suggest that AKAP6 plays an indispensable role in the function of the LINC complex in cardiomyocytes.