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Credit: Egelberg
Investigators say they have solved the mystery of an enzyme’s role in cell survival, thereby offering clues as to how the immune system fights infection and pointing to possible strategies for treating cancers.
The enzyme, receptor-interacting protein kinase 1 (RIPK1), is known to play a pivotal role in survival after birth.
But the new research, published in Cell, reveals that RIPK1 inhibits the pathways that control apoptosis and necroptosis.
By removing different components of each pathway in different combinations, the investigators demonstrated that, after birth, RIPK1 helps cells maintain a balanced response to signals that promote either pathway.
“We are learning that, in disease, this balancing act can be perturbed to produce damage and cell death,” said study author Douglas Green, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.
The results resolve long-standing questions about RIPK1’s role in cell survival and provide clues about how the immune system might use these pathways to contain infections.
The findings have also prompted the researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development.
“This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life,” Dr Green said. “The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these pathways or engage them in other ways to advance treatment of a range of diseases.”
The report builds on previous research from Dr Green’s lab regarding regulation of the pathways that control apoptosis and necroptosis. The investigators knew that apoptosis is driven by the enzyme caspase-8, which forms a complex with FADD and other proteins.
And necroptosis involves a pathway orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Before birth, RIPK1 works through RIPK3 to trigger cell death by necroptosis, but, until now, the enzyme’s primary role after birth was uncertain.
So the investigators bred mice lacking different combinations of genes for RIPK1, RIPK3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.
Mice lacking RIPK1 died. Mice missing 2 genes—RIPK1 plus RIPK3 or RIPK1 plus caspase-8 or FADD—also died soon after birth.
However, mice survived and developed normally when the investigators removed 3 genes—RIPK1, RIPK3, and either caspase-8 or FADD.
“The fact that the mice survived was totally unexpected and made us rethink how these pathways work,” Dr Green said.
The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis.
Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections. 
Credit: Egelberg
Investigators say they have solved the mystery of an enzyme’s role in cell survival, thereby offering clues as to how the immune system fights infection and pointing to possible strategies for treating cancers.
The enzyme, receptor-interacting protein kinase 1 (RIPK1), is known to play a pivotal role in survival after birth.
But the new research, published in Cell, reveals that RIPK1 inhibits the pathways that control apoptosis and necroptosis.
By removing different components of each pathway in different combinations, the investigators demonstrated that, after birth, RIPK1 helps cells maintain a balanced response to signals that promote either pathway.
“We are learning that, in disease, this balancing act can be perturbed to produce damage and cell death,” said study author Douglas Green, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.
The results resolve long-standing questions about RIPK1’s role in cell survival and provide clues about how the immune system might use these pathways to contain infections.
The findings have also prompted the researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development.
“This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life,” Dr Green said. “The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these pathways or engage them in other ways to advance treatment of a range of diseases.”
The report builds on previous research from Dr Green’s lab regarding regulation of the pathways that control apoptosis and necroptosis. The investigators knew that apoptosis is driven by the enzyme caspase-8, which forms a complex with FADD and other proteins.
And necroptosis involves a pathway orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Before birth, RIPK1 works through RIPK3 to trigger cell death by necroptosis, but, until now, the enzyme’s primary role after birth was uncertain.
So the investigators bred mice lacking different combinations of genes for RIPK1, RIPK3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.
Mice lacking RIPK1 died. Mice missing 2 genes—RIPK1 plus RIPK3 or RIPK1 plus caspase-8 or FADD—also died soon after birth.
However, mice survived and developed normally when the investigators removed 3 genes—RIPK1, RIPK3, and either caspase-8 or FADD.
“The fact that the mice survived was totally unexpected and made us rethink how these pathways work,” Dr Green said.
The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis.
Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections.
Credit: Egelberg
Investigators say they have solved the mystery of an enzyme’s role in cell survival, thereby offering clues as to how the immune system fights infection and pointing to possible strategies for treating cancers.
The enzyme, receptor-interacting protein kinase 1 (RIPK1), is known to play a pivotal role in survival after birth.
But the new research, published in Cell, reveals that RIPK1 inhibits the pathways that control apoptosis and necroptosis.
By removing different components of each pathway in different combinations, the investigators demonstrated that, after birth, RIPK1 helps cells maintain a balanced response to signals that promote either pathway.
“We are learning that, in disease, this balancing act can be perturbed to produce damage and cell death,” said study author Douglas Green, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.
The results resolve long-standing questions about RIPK1’s role in cell survival and provide clues about how the immune system might use these pathways to contain infections.
The findings have also prompted the researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development.
“This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life,” Dr Green said. “The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these pathways or engage them in other ways to advance treatment of a range of diseases.”
The report builds on previous research from Dr Green’s lab regarding regulation of the pathways that control apoptosis and necroptosis. The investigators knew that apoptosis is driven by the enzyme caspase-8, which forms a complex with FADD and other proteins.
And necroptosis involves a pathway orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Before birth, RIPK1 works through RIPK3 to trigger cell death by necroptosis, but, until now, the enzyme’s primary role after birth was uncertain.
So the investigators bred mice lacking different combinations of genes for RIPK1, RIPK3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.
Mice lacking RIPK1 died. Mice missing 2 genes—RIPK1 plus RIPK3 or RIPK1 plus caspase-8 or FADD—also died soon after birth.
However, mice survived and developed normally when the investigators removed 3 genes—RIPK1, RIPK3, and either caspase-8 or FADD.
“The fact that the mice survived was totally unexpected and made us rethink how these pathways work,” Dr Green said.
The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis.
Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections.