Orchestration of Force Generation and Nuclear Collapse in Apoptotic Cells.

Bruno Monier,Magali Suzanne

doi:10.3390/ijms221910257

Abstract

Apoptosis, or programmed cell death, is a form of cell suicide that is extremely important for ridding the body of cells that are no longer required, to protect the body against hazardous cells, such as cancerous ones, and to promote tissue morphogenesis during animal development. Upon reception of a death stimulus, the doomed cell activates biochemical pathways that eventually converge on the activation of dedicated enzymes, caspases. Numerous pieces of information on the biochemical control of the process have been gathered, from the successive events of caspase activation to the identification of their targets, such as lamins, which constitute the nuclear skeleton. Yet, evidence from multiple systems now shows that apoptosis is also a mechanical process, which may even ultimately impinge on the morphogenesis of the surrounding tissues. This mechanical role relies on dramatic actomyosin cytoskeleton remodelling, and on its coupling with the nucleus before nucleus fragmentation. Here, we provide an overview of apoptosis before describing how apoptotic forces could combine with selective caspase-dependent proteolysis to orchestrate nucleus destruction.

Highlights

The nucleus, which is the biggest and stiffest cell organelle, is kept apart from the cytoplasm by the nuclear envelope
The lamina is connected to the cytoskeleton through a macromolecular complex, known as the LINC (Linker of nucleoskeleton and cytoskeleton) complex, that spans the nuclear envelope [6]
The LINC is a bipartite complex composed of nesprin and SUN proteins, respectively, embedded in the external and internal nuclear envelope, and interacting in the space between those two membranes

Summary

Introduction

The nucleus, which is the biggest and stiffest cell organelle, is kept apart from the cytoplasm by the nuclear envelope. Nuclear envelope ruptures coincide with chromatin protrusion, DNA damage and nuclear fragmentation [24,25] These ruptures are associated with the assembly of contractile actin bundles and depend on the contractile activity of actomyosin and the integrity of the LINC complex [25,26]. One may hypothesise that increasing tension through caspase-dependent myosin activation and connection of the cytoskeleton to the nuclear envelope will speed up DNA fragmentation, eventually facilitating DNA fragmentation The observation of these blebs in apoptotic cells and in constrained migrating cells suggests that the formation of nuclear bubbles could be a general mechanism induced in response to stress. Local weakening of the nuclear lamina and nuclear opening occur in stress conditions but could contribute to the regulation of chromatin condensation during differentiation

Nuclear Dismantling

Actomyosin-Nucleus Coupling before Fragmentation

Could Apoptotic Microtubules Also Contribute to Nuclear Fragmentation?

A Necessity to Understand Nuclear Mechanotransduction during Cell Death

Conclusions