Stress granules are believed to play a critical role in modulating gene expression programs in response to environmental and nutrient stresses. However, it has been unclear how changes in cellular activity regulate stress granule formation and composition. The authors of a recent article, shown that Sam1 is recruited to yeast stress granules in response to a specific nutrient stress.
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM-e is produced and consumed in the liver. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase.
The scientists found that the product of Sam1, AdoMet, regulates stress granule formation in both yeast and human cells (HeLa and U2OS). This suggests that the connections between metabolism and stress granule assembly might be broader than previously believed. Their focus on the product of Sam1, AdoMet, uncovered parallels between how metabolites regulate metabolism and stress granule formation/composition. Most provocatively, AdoMet administration to iPSC-derived motor neurones cells, suppressed stress granule formation that expressed mutated forms of TDP-43 and FUS found in ALS patients. AdoMet was effective in blocking stress granule assembly in these disease models.
Cells deploy a variety of mechanisms to fine-tune biochemical processes in response to environmental stressors. One of these mechanisms is the formation of stress granules. Stress granules assemble in response to a variety of nutrient and metabolic stresses and are believed to provide a mechanism for coupling metabolic stress to post-transcriptional gene regulation.
Furthermore, stress granules act as centers to regulate cell signaling outputs and protein folding, highlighting stress granules as global integrators of the stress response. stress granules are transient and require tight regulation of both assembly and disassembly for cell function and viability. For example, disruption of stress granule formation decreases cell survival when the stress is removed.
In addition to their role in integrating the cellular stress response, stress granules have been implicated in a variety of neurodegenerative disorders. Dysregulation in stress granule dynamics in ALS patients results in accumulation of atypical cytoplasmic, stress granule-like protein aggregates in dying neurons of the brain and spinal cord. These results argue that understanding how stress granules assemble in response to metabolic or nutrient stresses is critical for both understanding the pathophysiology of ALS and FTD and developing treatment strategies focused on disrupting the formation of aberrant stress granules.
Given the linkage between stress granules and several neurodegenerative diseases, the composition of the stress granule proteome has been a subject of intense focus to identify potential therapeutic targets. Unfortunately, large-scale biochemical studies have found that stress granule composition is not only stress specific, but also organism and cell type specific. Although different techniques have helped identify which components reside within each phase, the relative role of stress granule core proteins and shell proteins in stress granule formation and pathogenesis remains unclear.
Despite the fact that stress granule formation and composition is stress specific, there has been surprisingly little exploration of the connections between metabolism and stress granule assembly. To date, only a few metabolic enzymes have been shown to be enriched or localized to stress granules via proteomic and/or targeted studies. This deficit is likely due to the limited number of stress conditions that have been used in stress granule proteomic studies. Interestingly, the localization of one metabolic enzyme, pyruvate kinase (Cdc19), to stress granules has been shown to be crucial for reactivation of growth-promoting pathways upon removal of stress. This suggests that stress granules can play a critical role in regulating metabolic enzymes in response to stress.
There are also limited examples of the reverse mode of regulation: metabolic intermediates that modulate stress granule assembly. Whereas stress granules can assemble upon the removal of glucose or amino acids, only one metabolite from intermediate metabolism, acetyl-CoA, has been implicated in regulating stress granule formation. Thus, the identification of metabolic enzymes that are recruited to stress granules in a stress-specific manner would identify new linkages between stress granule formation and metabolism as well as provide a novel set of potential therapeutic targets for ALS and FTD.
In this article the researchers have identified 17 metabolic enzymes that are recruited to yeast stress granules in a stress-specific manner. S-adenosylmethionine (AdoMet), the product of one these enzymes, is a regulator of stress granule assembly and composition.
The regulation of yeast stress granule formation by AdoMet is biphasic, with chronic changes altering stress granule composition and acute elevation of AdoMet suppressing stress granule assembly. Additionally, acute elevation of AdoMet suppresses stress granule formation in motor neurones, demonstrating conserved metabolite regulation of stress granule assembly from yeast to humans. The suppressive effect of AdoMet on stress granule formation also occurs in induced pluripotent stem cell (iPSC)-derived motor neurones from ALS patients.
AdoMet blocks the recruitment of cytoplasmic TDP-43 to remnant stress granules in this cell culture, implying that AdoMet can modify the pathogenic accumulation of stress granule material. Together, these results argue that metabolic activity controls both the composition and extent of stress granule formation and provide a framework for the identification of lead compounds that can modify or suppress stress granule formation.
Recent work on the stress granule proteome suggests that stress granule composition can vary depending on the cell type and the nature of the stress. Because many of the stresses that trigger stress granule assembly are thought to alter metabolic activity, either directly or indirectly, one might expect metabolic enzymes to be a common component of stress granules. However, few metabolic enzymes have been identified in proteomic and targeted studies of Saccharomyces cerevisiae stress granules. Their identification of 17 metabolic enzymes that are recruited to stress granules in response to physiological nutrient stresses, but are not recruited to stress granules in response to multiple acute stresses, argues that stress granule composition is tailored to the nature of the stress and that chronic stresses might require reorganization of the metabolic network.
This result also helps to explain why no metabolic enzymes have been identified in previous proteomic studies of mammalian stress granules. All of the stresses that are traditionally used to induce mammalian stress granules, such as sodium azide, do not trigger the recruitment of metabolic enzymes to yeast stress granules. Thus, one might expect to observe metabolic enzymes only in stress granules that assemble in response to the mammalian equivalent of a stationary-phase nutrient stress.
As a final thought: Whose ALS patient, have not dream of a simple drug that would alleviate their symptoms? AdoMet is interesting to investigate.