Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells.
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.
Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, Melbourne, Victoria 3004, Australia andre.laval.samson@gmail.com andre.samson@hri.org.au.|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.
Andre L
0000-0002-0637-2716
AL
Samson
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Bosco
B
Ho
Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, Melbourne, Victoria 3004, Australia.
Amanda E
AE
Au
Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, Melbourne, Victoria 3004, Australia.|Heart Research Institute, and Charles Perkins Centre, University of Sydney, Camperdown, New South Wales 2006, Australia.
Simone M
SM
Schoenwaelder
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.
Mark J
MJ
Smyth
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Stephen P
SP
Bottomley
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.|Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
Oded
O
Kleifeld
Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, Melbourne, Victoria 3004, Australia.
Robert L
RL
Medcalf
D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D005047:Etoposide / Q000633:toxicity*; D053222:Fas Ligand Protein / Q000633:toxicity; D006801:Humans; D019169:Jurkat Cells; D066329:Protein Aggregates; D020543:Proteome / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D019311:Staurosporine / Q000633:toxicity*
D053222:Fas Ligand Protein; D066329:Protein Aggregates; D020543:Proteome; D005047:Etoposide; D019311:Staurosporine
RNA-binding protein FUS; disulfide; immune tolerance; necrosis; protein aggregation; proteomics