title: 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.
authors.affiliation: Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Wu
authors.forename: Hai
authors.initials: H
authors.lastname: Jiang
authors.forename: Shouqing
authors.initials: S
authors.lastname: Luo
authors.forename: Mingsheng
authors.initials: M
authors.lastname: Zhang
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004260:DNA Repair; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008870:Microtubules / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins
chemical_list: C405928:CDK5RAP3 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D020169:Caspases