Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope

Abstract

Apoptotic nucleus undergoes distinct morphological and biochemical changes including nuclear shrinkage, chromatin condensation and DNA fragmentation, which are attributed to caspase-mediated cleavage of several nuclear substrates such as lamins. As most of active caspases reside in the cytoplasm, disruption of the nuclear-cytoplasmic barrier is essential for caspases to reach their nuclear targets. The prevailing proposed mechanism is that the increase in the permeability of nuclear pores induced by caspases allows the caspases and other apoptotic factors to diffuse into the nucleus, thereby resulting in the nuclear destruction. Here, we report a novel observation that physical rupture of the nuclear envelope (NE) occurs in the early stage of apoptosis. We found that the NE rupture was caused by caspase-mediated cleavage of C53/LZAP, a protein that has been implicated in various signaling pathways, including NF-κB signaling and DNA damage response, as well as tumorigenesis and metastasis. We also demonstrated that C53/LZAP bound indirectly to the microtubule (MT), and expression of the C53/LZAP cleavage product caused abnormal MT bundling and NE rupture. Taken together, our findings suggest a novel role of C53/LZAP in the regulation of MT dynamics and NE structure during apoptotic cell death. Our study may provide an additional mechanism for disruption of the nuclear-cytoplasmic barrier during apoptosis.

Structural and functional analysis of cell adhesion and nuclear envelope nano-topography in cell death

“…The disruption of nuclear scaffold (also known as nuclear matrix) proteins, such as lamins and the NPC, is increased in apoptotic cell death 28 . A recent study showed that caspase mediated the induction of NE disruption during apoptosis, and the results were confirmed through fluorescence intensity, measured by confocal microscopy 29 . However, the changes that occur in cell adhesion and the NE, and how these alterations and characteristics correlate to necrotic and apoptotic cell death, are not clearly understood.…”

“…Structural analysis of ESCs showed the presence of irregular and wide-shaped NEs in the intermembrane space of ESCs, in comparison to differentiated cells, through use of fluorescence staining and electron microscopy 55 . Further, apoptotic cell death showed disassembling of NE proteins, and structural changes in nucleus, such as shrinkage, NE rupture, irregular nucleus shape, and DNA leakage, which were measured by fluorescence staining and electron microscopy 29 56 57 . However, the study of structural and topographical changes of the NE using morphometric analysis is not ideal, due to the indirect detection of change by current methods, and the detection of only partial changes.…”

DSePA Antagonizes High Glucose-Induced Neurotoxicity: Evidences for DNA Damage-Mediated p53 Phosphorylation and MAPKs and AKT Pathways

“…After all, PC12 cell line is a cancer cell line, the in vivo effect and mechanism of DSePA need further evaluation. Apoptosis, a programmed cell death, plays an essential role in maintaining the homeostasis in the brain [32,33]. Caspase, a family of cysteine proteases, can be activated in response to apoptotic stimuli and play essential roles in launching cell apoptosis [34,35].…”

RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis

“…40 Furthermore, C53 protein, one of RCAD downstream targets, has been shown to be a microtubule-binding protein. 41 C53 KO leads to cell cycle defects and early embryonic lethality, 42 and depletion of C53 protein in tissue culture cells dramatically decreases the numbers of several types of intracellular vesicles (our unpublished observation). Therefore, we postulate that the RCAD/C53/DDRGK1 complex has an important role in regulation of intracellular vesicle trafficking.…”