Extracellular and Intracellular Skeletons: How Do They Involve in Apoptosis.

Apoptosis plays a key role in removing abnormal or senescent cells, maintaining the overall health of the tissue, and coordinating individual development. Recently, it has been discovered that the intracellular cytoskeleton plays a role in the apoptotic process. In addition, the regulatory role of extracellular matrix (ECM) fibrous proteins, which can be considered as the extracellular skeleton, in the process of apoptosis is rarely summarized. In this review, we collect the latest knowledge about how fibrous proteins inside and outside cells regulate apoptosis. We describe how ECM fibrous proteins participate in the regulation of death receptor and mitochondrial pathways through various signaling cascades mediated by integrins. We then explore the molecular mechanisms by which intracellular intermediate filaments regulate cell apoptosis by regulating death receptors on the cell membrane surface. Similarly, we report on novel supporting functions of microtubules in the execution phase of apoptosis and discuss their formation mechanisms. Finally, we discuss that the polypeptide fragments formed by caspase degradation of ECM fibrous proteins and intracellular intermediate filament act as local regulatory signals to play different regulatory roles in apoptosis.

Dynamic Reorganization of the Cytoskeleton during Apoptosis: The Two Coffins Hypothesis.

During apoptosis, cells undergo characteristic morphological changes in which the cytoskeleton plays an active role. The cytoskeleton rearrangements have been mainly attributed to actinomyosin ring contraction, while microtubule and intermediate filaments are depolymerized at early stages of apoptosis. However, recent results have shown that microtubules are reorganized during the execution phase of apoptosis forming an apoptotic microtubule network (AMN). Evidence suggests that AMN is required to maintain plasma membrane integrity and cell morphology during the execution phase of apoptosis. The new "two coffins" hypothesis proposes that both AMN and apoptotic cells can adopt two morphological patterns, round or irregular, which result from different cytoskeleton kinetic reorganization during the execution phase of apoptosis induced by genotoxic agents. In addition, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocyte responses. These findings suggest that knowing the type of apoptosis may be important to predict how fast apoptotic cells undergo secondary necrosis and the subsequent immune response. From a pathological point of view, round-shaped apoptosis can be seen as a physiological and controlled type of apoptosis, while irregular-shaped apoptosis can be considered as a pathological type of cell death closer to necrosis.