The dynamic nuclear envelope: resilience in health and dysfunction in disease

Abstract

The canonical appearance of the nucleus depends on constant adaptation and remodeling of the nuclear envelope in response to changing biomechanical forces and metabolic demands. Dynamic events at the nuclear envelope play a vital role in supporting key nuclear functions as well as conferring plasticity to this organelle. Moreover, imbalance of these dynamic processes is emerging as a central feature of disease etiology. This review focuses on recent advances that shed light on the myriad events at the nuclear envelope that contribute to resilience and flexibility in nuclear architecture.

Figure 1.. The canonical structure of the nucleus and the dynamic processes that function to maintain it.

A) The main elements of nuclear architecture and the nuclear envelope (NE), as well as the continuity of the NE with the endoplasmic reticulum (ER), are indicated. Outer nuclear membrane, ONM; inner nuclear membrane, INM; nuclear pore complex, NPC. Colored spheres represent INM associated proteins, including lipid synthesizing enzymes (orange) and those proteins destined for turnover (purple). B) A wide range of dynamic processes at the NE are illustrated. A variety of protein turnover processes maintain the INM proteome. Excess or mis-assembled protein complexes can be extracted from the INM and undergo nuclear proteasomal degradation, in a process termed INM-associated degradation or INMAD. Integral membrane proteins, as well as NPCs themselves, can also be removed by NE budding and targeted for autophagy. Certain integral membrane proteins diffuse laterally in NPC-associated membrane for degradation in the ER. The flow of lipids synthesized in the ER also occurs at membranes where NPCs are situated. Restraints on NE growth indicate a barrier to lipid diffusion exists at NPCs and perhaps at ER-NE junctions. Lipid synthesizing enzymes associated with the INM also function to generate lipids that are incorporated into the INM. Blebbing of the NE occurs upon imbalance of forces and can lead to nuclear rupture. Robust mechanisms of nuclear rupture repair help to maintain the canonical structure and integrity of the nucleus. Invaginations of the NE form Type I and Type II nuclear reticulum. Features of the NE are also influenced by biomechanical forces, which result in alignment of actin filaments, ONM and INM proteins, and lamin proteins, along with NPCs. Actin/LINC/Lamin, ALL; Transmembrane Actin-associated Nuclear, TAN.

Figure 2.. Nuclear envelope remodeling under physiological and pathological conditions.

A) Dynamic processes at the NE underpin physiological responses and homeostasis. Maintenance of appropriate levels of INM proteins is required for normal nuclear morphology. Nuclear ruptures/holes play a role in developmental processes such as erythroblast enucleation and potentially cardiomyoblast maturation. Nuclear invaginations, in many cases nuclear reticulum (NR), are associated with various physiological functions, such as gene expression, DNA repair and calcium signaling. Connectivity of actin cytoskeleton with the proteins at the NE promotes cell migration. Nuclear budding occurs in response to cell stress and in ongoing quality control. B) Under various pathological conditions dynamic processes involved in maintaining nuclear architecture go awry. Disease-associated mutations in NE associated proteins can result in both instability (LBR, emerin) or stabilization (Progerin/Lamin A). Elevated levels of blebbing, which can be caused by actin contraction, and rupture lead to loss of nuclear integrity in cancer and other diseases (see Table 1). Disease-associated mutations in tau cause a spectrum of neurological disease characterized by heightened formation of nuclear reticulum, in some cases driven by microtubules. Torsin dystonia is characterized by the accumulation of budding intermediates resulting from defects in NPC formation.