Fig. 2

The Role of Nesprin in LINC Complex Formation and Nuclear-Cytoskeletal Connectivity. A Nesprin plays a pivotal role in facilitating the formation of the LINC complex and establishing connectivity between the nucleus and the cytoskeleton. Nesprin proteins interact with SUN domain proteins, facilitating the physical connection between the nucleus and the cytoskeleton and enabling crucial cellular processes such as mechanotransduction, nuclear positioning, and intracellular signaling. Through its various isoforms and domain structures, Nesprin exhibits specific affinities for different cytoskeletal components, including actin filaments, intermediate filaments, and microtubules, further contributing to the versatility and functionality of the LINC complex in maintaining cellular integrity and homeostasis. Additionally, the LINC complex mediates chromatin binding through interactions with the nuclear lamina. Giant Nesprin-1/2 directly interfaces the nucleus with the actin cytoskeleton, while shorter Nesprin isoforms like Nesprin-1α₂ associate with microtubules via KLC-1/2 and AKAP6. AKAP6, in turn, tethers centrosomal proteins such as PCM-1 and AKAP9 to the nuclear membrane, forming a cAMP-PKA signaling hub that may regulate nuclear envelope calcium dynamics through interactions with RyR on the sarcoplasmic reticulum. B Mutations in Nesprin can disrupt the LINC complex, uncoupling the cytoskeleton from the nucleus and inducing structural aberrations such as abnormal nuclear morphology, size, migration, or positioning. This perturbation can trigger the activation of signaling cascades and mechanosensitive transcription factors, ultimately resulting in cellular dysfunction