title: Nucleocytoplasmic coagulation: an injury-induced aggregation event that disulfide crosslinks proteins and facilitates their removal by plasmin.
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 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.
authors.affiliation: Australian Centre for Blood Diseases, AMREP, Monash University, Melbourne, Victoria 3004, Australia. andre.samson@monash.edu
authors.forename: Andre L
authors.initials: AL
authors.lastname: Samson
authors.forename: Anja S
authors.initials: AS
authors.lastname: Knaupp
authors.forename: Maithili
authors.initials: M
authors.lastname: Sashindranath
authors.forename: Rachael J
authors.initials: RJ
authors.lastname: Borg
authors.forename: Amanda E-L
authors.initials: AE
authors.lastname: Au
authors.forename: Elisa J
authors.initials: EJ
authors.lastname: Cops
authors.forename: Helen M
authors.initials: HM
authors.lastname: Saunders
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Cody
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Hughes
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004220:Disulfides / Q000737:chemistry; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
chemical_list: D004220:Disulfides; D014404:Tubulin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin