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Open Biol. 2016 Nov;6(11). pii: 160098.

Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells.

Author information

Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, Melbourne, Victoria 3004, Australia
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Heart Research Institute, and Charles Perkins Centre, University of Sydney, Camperdown, New South Wales 2006, Australia.
Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, Melbourne, Victoria 3004, Australia.
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.


Amyloidogenic protein aggregation impairs cell function and is a hallmark of many chronic degenerative disorders. Protein aggregation is also a major event during acute injury; however, unlike amyloidogenesis, the process of injury-induced protein aggregation remains largely undefined. To provide this insight, we profiled the insoluble proteome of several cell types after acute injury. These experiments show that the disulfide-driven process of nucleocytoplasmic coagulation (NCC) is the main form of injury-induced protein aggregation. NCC is mechanistically distinct from amyloidogenesis, but still broadly impairs cell function by promoting the aggregation of hundreds of abundant and essential intracellular proteins. A small proportion of the intracellular proteome resists NCC and is instead released from necrotic cells. Notably, the physicochemical properties of NCC-resistant proteins are contrary to those of NCC-sensitive proteins. These observations challenge the dogma that liberation of constituents during necrosis is anarchic. Rather, inherent physicochemical features including cysteine content, hydrophobicity and intrinsic disorder determine whether a protein is released from necrotic cells. Furthermore, as half of the identified NCC-resistant proteins are known autoantigens, we propose that physicochemical properties that control NCC also affect immune tolerance and other host responses important for the restoration of homeostasis after necrotic injury.


RNA-binding protein FUS; disulfide; immune tolerance; necrosis; protein aggregation; proteomics

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