Nucleocytoplasmic Coagulation: An Injury-Induced Aggregation Event that Disulfide Crosslinks Proteins and Facilitates Their Removal by Plasmin

• Published in: Cell reports (Cambridge) Vol. 2; no. 4; pp. 889 - 901
• Main Authors: Samson, Andre L., Knaupp, Anja S., Sashindranath, Maithili, Borg, Rachael J., Au, Amanda E.-L., Cops, Elisa J., Saunders, Helen M., Cody, Stephen H., McLean, Catriona A., Nowell, Cameron J., Hughes, Victoria A., Bottomley, Stephen P., Medcalf, Robert L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2012; Elsevier
• Subjects: Animals; Apoptosis; Cells, Cultured; Disulfides - chemistry; Fibrinolysin - metabolism; Humans; Lymphocytes - immunology; Lymphocytes - metabolism; Male; Mice; Mice, Inbred C57BL; Neurons - cytology; Neurons - metabolism; Plasminogen - metabolism; Proteolysis - drug effects; Tissue Plasminogen Activator - pharmacology; Tubulin - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.08.026

Cellular injury causes a myriad of processes that affect proteostasis. We describe nucleocytoplasmic coagulation (NCC), an intracellular disulfide-dependent protein crosslinking event occurring upon late-stage cell death that orchestrates the proteolytic removal of misfolded proteins. In vitro and in vivo models of neuronal injury show that NCC involves conversion of soluble intracellular proteins, including tubulin, into insoluble oligomers. These oligomers, also seen in human brain tissue following neurotrauma, act as a cofactor and substrate for the plasminogen-activating system. In plasminogen−/− mice, levels of misfolded β-tubulin were elevated and its clearance delayed following neurotrauma, demonstrating a requirement for plasminogen in the removal of NCC constituents. While additional in vivo studies will further dissect this phenomenon, our study clearly shows that NCC, a process analogous to the formation of thrombi, generates an aggregated protein scaffold that limits release of cellular components and recruits clearance mechanisms to the site of injury. [Display omitted] ► Cell death triggers the process of nucleocytoplasmic coagulation (NCC) ► NCC is the abrupt misfolding and disulfide crosslinking of intracellular proteins ► NCC-aggregated proteins facilitate plasmin formation and subsequent proteolysis ► Thus, NCC limits release and promotes proteolytic clearance of dead cell debris During cell death, intracellular proteins become exposed to the extracellular environment, undergo conformational change, and are ultimately cleared. Samson, Medcalf, and colleagues now describe a protein aggregation event during the late stage of cell death referred to as nucleocytoplasmic coagulation (NCC). NCC results in the formation of insoluble oligomers that are dependent upon disulfide crosslinking. NCC is shown to provide a template mechanism for plasmin-dependent removal of NCC constituents in a process analogous to the proteolytic removal of blood clots.