Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells.
AuthorSamson, AL; Ho, B; Au, AE; Schoenwaelder, SM; Smyth, MJ; Bottomley, SP; Kleifeld, O; Medcalf, RL
Source TitleOpen Biology
PublisherThe Royal Society
University of Melbourne Author/sAu, Amanda
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsSamson, A. L., Ho, B., Au, A. E., Schoenwaelder, S. M., Smyth, M. J., Bottomley, S. P., Kleifeld, O. & Medcalf, R. L. (2016). Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells.. Open Biol, 6 (11), pp.160098-160098. https://doi.org/10.1098/rsob.160098.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133435
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.
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