The chains of stress recovery

doi:10.1126/science.abj2400

GSTDTAP > 气候变化

DOI	10.1126/science.abj2400
	The chains of stress recovery
	Dorothee Dormann
	2021-06-25
发表期刊	Science
出版年	2021
英文摘要	Cells often encounter stressful situations and respond to them with a stereotypical program to ensure survival. These responses involve increased expression of stress response factors, formation of stress granules (SGs), and shutting down of essential cellular processes, including RNA splicing, global translation, and nucleocytoplasmic transport. These adaptive changes are protective in the short term but need to be reversed once the stress has subsided so that cells can return to their normal activities. The molecular mechanisms involved in this reversal are only poorly understood. On pages 1409 and 1410 of this issue, Maxwell et al. ([ 1 ][1]) and Gwon et al. ([ 2 ][2]), respectively, reveal that recovery from heat stress requires tagging proteins with polyubiquitin chains. Together, these studies establish that ubiquitination has surprising regulatory and context-specific roles in the heat-stress response and emphasize that more attention should be paid to the stress recovery phase. A global increase in polyubiquitin conjugation in response to stress has long been noticed, but this was mainly considered to induce the degradation of damaged or misfolded proteins that arise during cellular stress. Maxwell et al. examined which proteins become ubiquitinated upon different types of stress, including heat shock (42°C), arsenite treatment, osmotic stress, ultraviolet irradiation, and proteasome inhibition. They found many stress-specific changes, revealing that certain proteins became ubiquitinated exclusively in response to heat shock, whereas a different set of proteins was ubiquitinated upon arsenite exposure. This indicated that stress-specific patterns of ubiquitination represent distinct adaptive responses that could have important roles in the stress response. Maxwell et al. dug deeper into the heatstress response. Using deep quantitative proteomic analyses, they identified ∼4900 proteins that showed an increase in ubiquitination following heat stress. They found that this “heat shock ubiquitinome” is highly enriched in proteins that function in processes that are down-regulated or shut down during cellular stress—e.g., translation, RNA splicing, nucleocytoplasmic transport, DNA damage repair, or the cell cycle. Among the heat shock ubiquitinome were also many proteins involved in the formation of SGs. These form when inhibition of translation leads to a rapid increase in untranslated cytoplasmic messenger RNA (mRNA). This triggers multicomponent liquid-liquid phase separation (LLPS) of mRNA with RNA binding proteins and gives rise to dynamic, reversible ribonucleoprotein (RNP) droplets in the cytoplasm. Upon removal of stress, SGs disassemble and translation resumes. Maxwell et al. found that numerous RNA binding proteins in SGs are polyubiquitinated after heat stress but not after arsenite stress. Thus, proteins involved in various stress-regulated pathways become specifically polyubiquitinated upon heat shock, suggesting that polyubiquitination could regulate these pathways. ![Figure][3] Ubiquitin controls stress granule disassembly after heat stress Upon heat stress, RNA binding proteins (RBPs) and messenger RNAs (mRNAs) coalesce to form stress granules, and the central stress granule protein Ras GTPase-activating protein–binding protein 1 (G3BP1) is tagged with polyubiquitin chains. In the subsequent stress recovery phase, polyubiquitinated G3BP1 is degraded by the proteasome, involving valosin-containing protein (VCP) and an endoplasmic reticulum–associated adaptor protein, leading to disassembly of stress granules. GRAPHIC: C. BICKEL/ SCIENCE Maxwell et al. suspected that ubiquitination could be particularly important in the stress recovery phase, because they observed that most of the ubiquitinated proteins were not degraded during heat stress but rather during subsequent recovery at 37°C. Using an inhibitor of the ubiquitin conjugation reaction, they demonstrated that ubiquitination is required for the reinitiation of translation, the reversal of heat shock–induced nuclear transport impairments, and SG dissolution. Collectively, these findings establish an essential role of ubiquitination in the recovery of cellular activities following heat stress. The authors furthermore noted that one of the proteins that became polyubiquitinated after heat stress is the central SG protein G3BP1 (Ras GTPase-activating protein–binding protein 1). The protein caught their attention because G3BP1 and its paralog G3BP2 are central nodes in the protein-RNA interaction network that leads to LLPS and SG assembly ([ 3 ][4]). Elimination of G3BP1 interferes with SG assembly, and G3BP1 overexpression or optogenetic induction of G3BP1 dimerization is sufficient to trigger SG formation in the absence of stress ([ 3 ][4], [ 4 ][5]). Could ubiquitination of G3BP1 followed by its degradation underlie SG disassembly during recovery from heat shock? Gwon et al. confirmed that G3BP1 undergoes K63-linked polyubiquitination after heat shock and is degraded by the proteasome during heat-stress recovery but not after other forms of stress. Using a mutational analysis, they were able to map the ubiquitin conjugation sites to the aminoterminal dimerization domain, which is crucial for RNA-dependent LLPS of G3BP1 ([ 3 ][4]). Cells expressing G3BP1 mutants that cannot be ubiquitinated showed severely delayed SG disassembly and featured less-dynamic SGs, which supports the idea that ubiquitination of G3BP1 is required for the dynamic disassembly of heat shock–induced SGs (see the figure). Additionally, Gwon et al. demonstrated that upon heat shock, polyubiquitinated G3BP1 interacts with the protein segregase VCP (valosin-containing protein), which is coupled to both proteasome- and autophagy-dependent degradation. They found that this interaction occurs through a cofactor with a ubiquitin-binding domain, FAF2 (FAS-associated factor 2), which is an endoplasmic reticulum (ER)–associated protein. They observed recruitment of G3BP1-, VCP-, and FAF2-positive SGs to the ER upon heat shock, which suggests that heat shock–induced SG disassembly occurs on the ER membrane. This underpins the idea that the cytosolic surface of the ER is an important nexus for coordinating the heat-stress response, including the integrated stress response, the unfolded protein response, ER-associated degradation, and, as now discovered by Gwon et al. , SG disassembly. The studies of Maxwell et al. and Gwon et al. illustrate that not all stresses are created equal. This has been recognized in other contexts—for example, SGs have distinct morphologies and composition depending on the type of stress ([ 5 ][6], [ 6 ][7]), and posttranslational modifications are often introduced in a stress-specific manner ([ 7 ][8]). The study by Maxwell et al. underscores this theme by demonstrating that different stressors generate distinct ubiquitination patterns. This explains why an earlier study using arsenite stress found ubiquitination to be dispensable for SG dynamics ([ 8 ][9]), whereas others have found an important role of small ubiquitin-like modifier (SUMO)–primed ubiquitination in the disassembly of heat stress–induced SGs ([ 9 ][10]). Gwon et al. found that even the duration of stress can have profoundly different consequences: Short (30 min) heat stress induces the formation of SGs that are fully disassembled during stress recovery, whereas prolonged (90 min) heat stress leads to persistent SGs that are cleared by autophagic degradation. This finding explains apparent discrepancies in the literature on the role of autophagy in SG clearance ([ 10 ][11], [ 11 ][12]). It also emphasizes that researchers should pay attention to disease-relevant contexts, including the use of specific cell types and exact type of stress. Dynamic posttranslational modifications have recently been appreciated as key regulators of LLPS and RNP granules—e.g., they can alter biomolecular interactions and thus determine the threshold at which a protein phase separates ([ 12 ][13]). Gwon et al. identify an additional mechanism to control the dynamics of RNP droplets in cells. Polyubiquitin-mediated degradation of key constituents of cellular RNP granules could be a general mechanism controlling the dynamics of such granules—e.g., some of the known stress-induced nuclear bodies. Moreover, Gwon et al. found that ubiquitination alters G3BP1 mobility within SGs, hence an interesting question to address in the future is whether polyubiquitin chains can directly affect the phase separation behavior of the modified proteins and thus alter RNP granule dynamics independent of proteasomal degradation. A role for polyubiquitin in protein phase separation and aggregation has been previously demonstrated ([ 13 ][14], [ 14 ][15]), so it seems possible that stress-induced polyubiquitination regulates RNP droplets also through degradation-independent mechanisms. Regulation of condensate dynamics is a particularly important topic in the context of neurodegenerative diseases, where impaired dynamics of RNP granules (e.g., SGs) are believed to promote aberrant LLPS and aggregation of disease-linked RNA binding proteins. Some of the aggregating proteins found in neurodegenerative disorders [e.g., TAR DNA binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS)] are highly polyubiquitinated in disease ([ 15 ][16]) and also were found by Maxwell et al. to become polyubiquitinated in the heat-stress response. This could prompt future studies on the role of ubiquitination of these disease-linked proteins and its relevance in the disease process. The studies of Maxwell et al. and Gwon et al. reveal interesting paradigms that require further research. For example, it will be interesting to determine how ubiquitination regulates the reversal of other heat shock–regulated processes, such as translation, splicing, or nuclear transport. Another topic to address is whether other SG proteins that become ubiquitinated upon heat shock contribute to the regulation of SGs and, if so, through which mechanisms. Finally, the role of ubiquitination in response to other types of stress—e.g., oxidative or genotoxic stress—remains to be resolved. The heat is on to find out. 1. [↵][17]1. B. A. Maxwell et al ., Science 372, eabc3593 (2021). [OpenUrl][18][Abstract/FREE Full Text][19] 2. [↵][20]1. Y. Gwon et al ., Science 372, eabf6548 (2021). [OpenUrl][21][Abstract/FREE Full Text][22] 3. [↵][23]1. P. Yang et al ., Cell 181, 325 (2020). [OpenUrl][24][CrossRef][25][PubMed][26] 4. [↵][27]1. P. Zhang et al ., eLife 8, e39578 (2019). 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334124
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Dorothee Dormann. The chains of stress recovery[J]. Science,2021.
APA	Dorothee Dormann.(2021).The chains of stress recovery.Science.
MLA	Dorothee Dormann."The chains of stress recovery".Science (2021).