Journal article

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

Andre L Samson, Anja S Knaupp, Maithili Sashindranath, Rachael J Borg, Amanda E-L Au, Elisa J Cops, Helen M Saunders, Stephen H Cody, Catriona A McLean, Cameron J Nowell, Victoria A Hughes, Stephen P Bottomley, Robert L Medcalf

Cell Reports | CELL PRESS | Published : 2012

Abstract

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 neur..

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Grants

Funding Acknowledgements

We thank Professor Charles G. Glabe for kindly providing the conformation-specific antibodies. Tissues were received from the Neurotrauma Tissue/Fluid Bank, supported by the Victorian Brain Bank Network, Mental Health Research Institute, The Alfred, National Trauma Research Institute, and Victorian Forensic Institute of Medicine and funded by Victorian Neurotrauma Initiative, the TAC, and Australia's NH&MRC. We thank Monash Biomedical Proteomic facility for peptide mass fingerprinting and Dr. Kris Hall for assistance with image processing. We thank the Burnet Institute (Victoria, Australia) for use of the Zeiss Cell Observer system. We acknowledge Mr. Be'eri Niego and Dr. Amy Robertson for constructive comments. This study was supported by grants awarded to A.L.S., S.P.B., and R.L.M. by the NH&MRC of Australia, by a Monash University Faculty of Medicine, Nursing and Health Sciences Strategic Grant awarded to A.L.S. and by an Australian Postgraduate Award and Faculty Postgraduate Scholarship awarded to A.E.-L.A. and R.J.B., respectively.