Maurizio Molinari’s group has published a study in Nature Communications revealing the mechanisms regulating nuclear envelope dynamics in response to induction and to resolution of pharmacologic stresses. Kucinska, M.K., et al (2023) Nature Comm. 14, 3497.
Bellinzona, June 27, 2023 – The nuclear envelope (NE) is a continuation of the endoplasmic reticulum (ER). In nucleated cells, it protects the genetic material with two membranes, the inner (INM) and outer nuclear membrane (ONM). The NE is highly dynamic. It undergoes deconstruction and reassembly during open mitosis and regulates the exchange of macromolecules between nucleoplasm and cytoplasm. Dysfunction in its structural assembly and dynamics is observed in tumors and laminopathies. The even distance between the INM and ONM that compose the NE is maintained by LINC complexes, which are formed by SUN proteins in the INM and NESPRIN proteins in the ONM covalently linked via disulfide bonds.
The study reveals that the adaptation of the NE structure to changes in cellular homeostasis (e.g., upon pharmacologic-induced cellular stress) requires disassembly of the LINC complexes by the ONM-resident TMX4 reductase. TMX4 reversibly detaches SUN from NESPRIN proteins thereby allowing the swelling of the ONM. Upon conclusion of the cellular stress, physiologic conditions are restored by selective autophagy (i.e., lysosomal clearance) of ONM portions, which involves the autophagy receptor SEC62, the LC3 lipidation machinery and the direct capture of ONM portions by degradative LAMP1/RAB7-positive endolysosomes.
Molinari’s Group is now exploring whether the mechanisms regulating NE dynamics are hijacked by viruses that perturb NE structure to promote egress of their capsid from the nucleoplasm during their infection cycle.
A) 3D reconstruction of ONM’s asymmetric vesiculation by room temperature electron tomography.
B) Isosurface representation of a cryo electron tomogram showing intact (INM:ONM distance <50nm) and reduced LINC complexes (INM:ONM >50nm).