Use the following information to answer questions: Prions in the cell are synonymous with disease. Misfolding of the mammalian prion protein (PrP) is at the root of the fatal neurodegenerative disease transmissible spongiform encephalopathies (TSE), which afflicts humans, cattle, sheep, deer, and other animals. Prions have also been implicated in Alzheimer's disease. There have been intense efforts to develop therapies for TSE, based on chemotherapeutics and antibodies, that would act by modulating the expression and stability of PrP, although it remains unclear whether the soluble, properly... Show more Use the following information to answer questions: Prions in the cell are synonymous with disease. Misfolding of the mammalian prion protein (PrP) is at the root of the fatal neurodegenerative disease transmissible spongiform encephalopathies (TSE), which afflicts humans, cattle, sheep, deer, and other animals. Prions have also been implicated in Alzheimer's disease. There have been intense efforts to develop therapies for TSE, based on chemotherapeutics and antibodies, that would act by modulating the expression and stability of PrP, although it remains unclear whether the soluble, properly folded form of PrP has important functions in the cell. Despite decades of research on the severity of prion-mediated disease in mammals, beneficial roles for the prion form of some proteins have recently been coming into view. The irreversible aggregation of proteins effectively results in robust amplification of immune signaling. There is also evidence that prions could be important for the formation of immune memory. Two examples of mammalian proteins that could be functional in their prion form are MAVS and ASC. MAVS aggregates in response to the highly sensitive binding of the RIG-I protein to viral RNA inside the cell. Following binding, RIG-I oligomerizes and activates MAVS, which in turn leads to the induction of antiviral cytokine expression. Several experimental findings first suggested that MAVS forms prions: the protein gathers into complexes that are resistant to treatment with 2% sodium dodecyl sulfate (SDS), and the addition of these complexes to recombinant MAVS proteins in vitro caused these proteins to form protease-resistant cores. Furthermore, the MAVS prion state can be propagated through cell divisions. Nevertheless MAVS does stand apart from other typical prions in several ways. For one, their polymerization leads to gain of function. In addition, their polymerization is not stochastic but in response to activation by upstream sensors. Still, the other prion-like qualities of MAVS qualify it to be in this group of proteins. Once MAVS is activated by RIG-I, it forms punctate structures in the cell that are thought to be important for recruiting other proteins that help propagate its signal. Although MAVS is one of the first gain-of-function prions to be described in mammalian cells, there is evidence that these types of proteins are evolutionarily conserved. For example, when the fungal protein HET-S protein converts from soluble to aggregated, it can signal cell death to surrounding cells that do not contain HET-S prions. This finding suggests that prion state could possibly act as a form of memory for the cell of previous infection or insult. There is speculation that mammalian prions could serve a similar function and help explain the mechanism whereby mammalian cells are desensitized to pathogen stimulation and other threats. Show less
Use the following information to answer questions:
Prions in the cell are synonymous with disease. Misfolding of the mammalian prion protein (PrP) is at the root of the fatal neurodegenerative disease transmissible spongiform encephalopathies (TSE), which afflicts humans, cattle, sheep, deer, and other animals. Prions have also been implicated in Alzheimer's disease. There have been intense efforts to develop therapies for TSE, based on chemotherapeutics and antibodies, that would act by modulating the expression and stability of PrP, although it remains unclear whether the soluble, properly folded form of PrP has important functions in the cell. Despite decades of research on the severity of prion-mediated disease in mammals, beneficial roles for the prion form of some proteins have recently been coming into view. The irreversible aggregation of proteins effectively results in robust amplification of immune signaling. There is also evidence that prions could be important for the formation of immune memory. Two examples of mammalian proteins that could be functional in their prion form are MAVS and ASC. MAVS aggregates in response to the highly sensitive binding of the RIG-I protein to viral RNA inside the cell. Following binding, RIG-I oligomerizes and activates MAVS, which in turn leads to the induction of antiviral cytokine expression. Several experimental findings first suggested that MAVS forms prions: the protein gathers into complexes that are resistant to treatment with 2% sodium dodecyl sulfate (SDS), and the addition of these complexes to recombinant MAVS proteins in vitro caused these proteins to form protease-resistant cores. Furthermore, the MAVS prion state can be propagated through cell divisions. Nevertheless MAVS does stand apart from other typical prions in several ways. For one, their polymerization leads to gain of function. In addition, their polymerization is not stochastic but in response to activation by upstream sensors. Still, the other prion-like qualities of MAVS qualify it to be in this group of proteins. Once MAVS is activated by RIG-I, it forms punctate structures in the cell that are thought to be important for recruiting other proteins that help propagate its signal.
Although MAVS is one of the first gain-of-function prions to be described in mammalian cells, there is evidence that these types of proteins are evolutionarily conserved. For example, when the fungal protein HET-S protein converts from soluble to aggregated, it can signal cell death to surrounding cells that do not contain HET-S prions. This finding suggests that prion state could possibly act as a form of memory for the cell of previous infection or insult. There is speculation that mammalian prions could serve a similar function and help explain the mechanism whereby mammalian cells are desensitized to pathogen stimulation and other threats.
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