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

Samson, Andre L., Ho, Bosco, Au, Amanda E., Schoenwaelder, Simone M., Smyth, Mark J., Bottomley, Stephen P., Kleifeld, Oded and Medcalf, Robert L. (2016) Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells. Open Biology, 6 11: . doi:10.1098/rsob.160098


Author Samson, Andre L.
Ho, Bosco
Au, Amanda E.
Schoenwaelder, Simone M.
Smyth, Mark J.
Bottomley, Stephen P.
Kleifeld, Oded
Medcalf, Robert L.
Title Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells
Journal name Open Biology   Check publisher's open access policy
ISSN 2046-2441
Publication date 2016-11-03
Sub-type Article (original research)
DOI 10.1098/rsob.160098
Open Access Status DOI
Volume 6
Issue 11
Total pages 12
Place of publication London, United Kingdom
Publisher Royal Society of London
Language eng
Subject 2800 Neuroscience
2403 Immunology
1300 Biochemistry, Genetics and Molecular Biology
Abstract 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 injuryinduced 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.
Keyword Disulfide
Immune tolerance
Necrosis
Protein aggregation
Proteomics
RNA-binding protein FUS
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Sub-type: Article (original research)
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