Tuning between Nuclear Organization and Functionality in Health and Disease

Abstract

The organization of eukaryotic genome in the nucleus, a double-membraned organelle separated from the cytoplasm, is highly complex and dynamic. The functional architecture of the nucleus is confined by the layers of internal and cytoplasmic elements, including chromatin organization, nuclear envelope associated proteome and transport, nuclear-cytoskeletal contacts, and the mechano-regulatory signaling cascades. The size and morphology of the nucleus could impose a significant impact on nuclear mechanics, chromatin organization, gene expression, cell functionality and disease development. The maintenance of nuclear organization during genetic or physical perturbation is crucial for the viability and lifespan of the cell. Abnormal nuclear envelope morphologies, such as invagination and blebbing, have functional implications in several human disorders, including cancer, accelerated aging, thyroid disorders, and different types of neuro-muscular diseases. Despite the evident interplay between nuclear structure and nuclear function, our knowledge about the underlying molecular mechanisms for regulation of nuclear morphology and cell functionality during health and illness is rather poor. This review highlights the essential nuclear, cellular, and extracellular components that govern the organization of nuclei and functional consequences associated with nuclear morphometric aberrations. Finally, we discuss the recent developments with diagnostic and therapeutic implications targeting nuclear morphology in health and disease.

Keywords: cancer; neurodegenerative disorders; nuclear envelope proteins; nuclear lamins; nuclear shape regulation; nuclear size regulation; nucleopathy; nucleophagy; signaling pathways; targeted therapy.

Figure 1

The constituents that contribute to regulation of morphology and characteristic organization of a common eukaryotic nucleus. The major components include the lamin network, nuclear envelope (NE), chromatin and membrane-less nuclear subcompartments. The lamin A/C and lamin B assemble around the inner nuclear membrane. Lamina and colocalized INM anchoring proteins, also known as tethering proteins (i.e., LBR, LEM, BAF, LAP, emerin, etc.), anchor at specific “lamina associated domains (LAD)” of the genome. The nuclear envelope associated components include nuclear pore complex (NPC) proteins (Nup) and the linker of nucleoskeleton and cytoskeleton (LINC) complex. Nup153 along with other membrane curvature sensing proteins (i.e., Pom) equilibrate the membrane shaping forces into the NPC assembly. Nup 153 also co-localize with Sun1 and POM121 proteins, which link the NPCs in nucleo-cytoskeletal network coupling and the mechanobiology of nuclear envelope. LINC physically connects the cytoskeletal framework to the nucleoplasmic filaments. The dynamic intermediate bridge of LINC includes INM anchored SUN domain protein and the ONM embedded KASH motif that interacts with the actin filaments, microtubule and intermediate filaments network using containing proteins, i.e., nesprin-1/2/3 and plectin, etc.; SUN domain proteins, meanwhile, bind to the NPC, lamina and chromatin using several intermediate tethering proteins. Specific INM proteins, such as Mps3, Scs2 and Opi1, contribute to lipid membrane biogenesis during morphological alteration of the nucleus. The nuclear subcompartments (Chromatin territories) are microenvironment created by the concentrate of specific proteins that contributes to the organization of different domains of chromatin fiber into the nuclear volume.

Figure 2

Nucleus contexture and interaction between nucleus and cytoplasmic content. The mechanical transduction of external forces affects nuclear morphology through interaction between nuclear matrix and cytoskeleton. The figure represents specific bonding between cytoplasmic macromolecules (actin, tubulin pectin, etc.) and nuclear LINC complex, lamins, SUN protein, KASH motif and nesprin protein. The physical interconnection involving the specific tethering contact of the nucleus with the membrane-bound organelles, such as ER, also plays an important role in nuclear positioning and regulation of its morphology.

Figure 3

Nuclear aberrations and functional abnormalities. Pathophysiology of related diseases and possible targets for the treatment.