Apoptosis leads to a degradation of vital components of active nuclear transport and a dissociation of the nuclear lamina

Abstract

Apoptosis, a physiologically critical process, is characterized by a destruction of the cell after sequential degradation of key cellular components. Here, we set out to explore the fate of the physiologically indispensable nuclear envelope (NE) in this process. The NE mediates the critical nucleocytoplasmic transport through nuclear pore complexes (NPCs). In addition, the NE is involved in gene expression and contributes significantly to the overall structure and mechanical stability of the cell nucleus through the nuclear lamina, which underlies the entire nucleoplasmic face of the NE and thereby interconnects the NPCs, the NE, and the genomic material. Using the nano-imaging and mechanical probing approach atomic force microscopy (AFM) and biochemical methods, we unveiled the fate of the NE during apoptosis. The doomed NE sustains a degradation of both the mediators of the critical selective nucleocytoplasmic transport, namely NPC cytoplasmic filaments and basket, and the nuclear lamina. These observations are paralleled by marked softening and destabilization of the NE and the detection of vesicle-like nuclear fragments. We conclude that destruction of the cell nucleus during apoptosis proceeds in a strategic fashion. Degradation of NPC cytoplasmic filaments and basket shuts down the critical selective nucleocytoplasmic cross-talk. Degradation of the nuclear lamina disrupts the pivotal connection between the NE and the chromatin, breaks up the overall nuclear architecture, and softens the NE, thereby enabling the formation of nuclear fragments at later stages of apoptosis.atomic force microscopy ͉ nuclear envelope ͉ nuclear pores ͉ nucleocytoplasmic transport

Influenza Virus-Induced Caspase-Dependent Enlargement of Nuclear Pores Promotes Nuclear Export of Viral Ribonucleoprotein Complexes

“…Previous studies suggest that caspase activation initiates a coordinated disruption of the nuclear lamina which, in IV-infected cells may increase the passive diffusion limit of nuclear pores and thereby facilitate migration of viral RNPs to the cytoplasm in late phases of the viral life cycle (11,16). The data presented above confirm and extend these hypotheses.…”

“…To further analyze the downstream effects of virus-induced caspase activation on nuclear RNP export, we focused on Nup153, a known caspase substrate and an important component of the NPC (16,48). We were able to show that IAV-triggered caspase activities caused a progressive degradation of this nuclear pore component (Fig.…”

“…Caspase activation is known to cause degradation of proteins of the NPC and disintegration of the nuclear basket that controls active export functions (16). One of the caspase 3/7 substrates was previously shown to be Nup153, an important component of the NPC nuclear basket and a key player in controlling nuclear import and export functions (31,32,40,41).…”

“…Caspases have a variety of cellular substrates. Of special interest in the context of this study is the role of caspases in the degradation of nuclear pore proteins and removal of the nuclear basket that controls active export functions of the nuclear pore complex (NPC) (16). NPCs are large, 125-MDa protein assemblies comprised of more than 30 proteins called nucleoporins (Nups) that together form an octagonal symmetrical structure (17)(18)(19)(20).…”

Nanomechanical resonators and their applications in biological/chemical detection: Nanomechanics principles

“…However, it should be noted that, during the cell's functions such as apoptosis, the functional cycle induces changes to not only the mass density but also the stiffness of the cell [156,157]. This indicates that it is also critical to measure the stiffness change for the cell using the micro/nanomechanical resonators in order to quantitatively understand the cell's function.…”