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.
Original language | English |
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Article number | 160098 |
Number of pages | 12 |
Journal | Biology Open |
Volume | 6 |
Issue number | 11 |
DOIs | |
Publication status | Published - 2016 |
Keywords
- Disulfide
- Immune tolerance
- Necrosis
- Protein aggregation
- Proteomics
- RNA-binding protein FUS
Equipment
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Monash Genome Modification Platform
Jeanette Rientjes (Manager) & Leanne Maree Hawkey (Manager)
Australian Regenerative Medicine InstituteFacility/equipment: Facility