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 |
|---|---|
| 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
Cite this
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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; Medcalf, Robert L.
In: Biology Open, Vol. 6, No. 11, 160098, 2016.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells
AU - Samson, Andre L.
AU - Ho, Bosco
AU - Au, Amanda E.
AU - Schoenwaelder, Simone M.
AU - Smyth, Mark J.
AU - Bottomley, Stephen P.
AU - Kleifeld, Oded
AU - Medcalf, Robert L.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Disulfide
KW - Immune tolerance
KW - Necrosis
KW - Protein aggregation
KW - Proteomics
KW - RNA-binding protein FUS
UR - http://www.scopus.com/inward/record.url?scp=84995912328&partnerID=8YFLogxK
U2 - 10.1098/rsob.160098
DO - 10.1098/rsob.160098
M3 - Article
VL - 6
JO - Biology Open
JF - Biology Open
SN - 2046-6390
IS - 11
M1 - 160098
ER -