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Abstract
Stress granules (SGs) are nonmembrane assemblies formed in cells in response to stress conditions. SGs mainly contain untranslated mRNA and a variety of proteins. RNAs and scaffold proteins with intrinsically disordered regions or RNA‐binding domains are essential for the assembly of SGs, and multivalent macromolecular interactions among these components are thought to be the driving forces for SG assembly. The SG assembly process includes regulation through post‐translational modification and involvement of the cytoskeletal system. During aging, many intracellular bioprocesses become disrupted by factors such as cellular environmental changes, mitochondrial dysfunction, and decline in the protein quality control system. Such changes could lead to the formation of aberrant SGs, as well as alterations in their maintenance, disassembly, and clearance. These aberrant SGs might in turn promote aging and aging‐associated diseases. In this paper, we first review the latest progress on the molecular mechanisms underlying SG assembly and SG functioning under stress conditions. Then, we provide a detailed discussion of the relevance of SGs to aging and aging‐associated diseases.
1 INTRODUCTION
Cells rely on distinct compartments and organelles, in which molecules are protected against other agents from the surrounding milieu, to concentrate specific cellular components for achieving specific biochemical reactions and biological functions (Aguilera‐Gomez & Rabouille, 2017). Most well‐known organelles are separated from their surroundings by a lipid membrane boundary, for example, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and peroxisomes. In addition, non‐membrane‐bound cytoplasmic and nuclear compartments have also been identified, and these compartments harbor RNAs and RNA‐binding proteins, including P bodies (Sheth & Parker, 2003), stress granules (SGs) (Arrigo, Suhan, & Welch, 1988; Collier & Schlesinger, 1986), germ granules (Eddy, 1975; Guraya, 1979; Voronina, Seydoux, Sassone‐Corsi, & Nagamori, 2011), neuronal transport granules (Knowles et al., 1996), Cajal bodies (Gall, Bellini, Wu, & Murphy, 1999), and the nucleolus (Brangwynne, Mitchison, & Hyman, 2011; Shaw & Jordan, 1995).
Stress granules are members of this emerging class of membraneless assemblies. They form when cells experience stress conditions, and are thought to influence cellular signaling pathways, and mRNA function, localization, and turn over (Buchan, 2014; Buchan & Parker, 2009; Kedersha, Ivanov, & Anderson, 2013). They present across eukaryotes, including mammalian, plant, and fungal (yeast) cells. In mammalian cells, SGs form in response to heat stress, arsenite exposure, UV irradiation, and viral infection (Kedersha et al., 2013). In plant cells, SGs are induced by hypoxia, high‐salt stress, and oxidative stress, as well as methyl jasmonate, potassium cyanide, and myxothiazol exposure (Gutierrez‐Beltran, Moschou, Smertenko, & Bozhkov, 2015; Nover, Scharf, & Neumann, 1983; Pomeranz et al., 2010; Sorenson & Bailey‐Serres, 2014; Weber, Nover, & Fauth, 2008; Yan, Yan, Wang, Yan, & Han, 2014). SGs form from pools of untranslated mRNA and contain various translation initiation factors, as well as a variety of RNA‐binding proteins and many non‐RNA‐binding proteins (Guzikowski, Chen, & Zid, 2019). SGs are dynamic, complex, and variable assemblies, with composition and structure that can vary dramatically under different types of stresses, such as heat shock, oxidative stress, osmotic stress, nutrient starvation, and UV irradiation. This diversity of SGs supposedly relies on diverse interactions between proteins and RNAs within the SGs and reflects the ability of cells to respond quickly to various environmental stresses (Buchan & Parker, 2009; Protter & Parker, 2016). Recent evidence has revealed that mammalian SGs show liquid‐like behavior while yeast SGs have characteristics similar to those of solid material (Kroschwald et al., 2015). Results from super‐resolution fluorescence microscopy and fluorescence recovery after photobleaching (FRAP) experiments reveal that SGs have two distinct layers with different components, functions, and dynamics: a stable inner core structure surrounded by a less dense shell layer. The components in the core structure are believed to be less dynamic, while the components in the shell layer are more dynamic. Two models were proposed for SG assembly. The first is that SG assembly is initiated by formation of a stable core containing a diverse proteome, followed by rapid growth of this core. Subsequently, these initial small granules merge to form larger mature stress granules, through liquid–liquid phase separation (LLPS). Alternatively, LLPS of translationally repressed ribonucleoproteins occurs first, and then, high concentrations of proteins in phase‐separated droplets promote the formation of the core (Jain et al., 2016; Wheeler, Matheny, Jain, Abrisch, & Parker, 2016).
2 STRESS GRANULE FORMATION AND REGULATION
Unlike cellular compartments surrounded by lipid bilayer membranes, which physically separate the interior and exterior of the compartments, SGs lack a physical barrier to separate their components from the surrounding medium. For many years, it remained elusive how molecules could be clustered into a discrete area without a surrounding barrier, and how such clustered molecules could modulate their structures and internal biochemical activities. Increasing evidence indicates that LLPS driven by multivalent weak macromolecular interactions (protein–protein, protein–RNA, and RNA‐RNA interactions) is an important organizing principle underlying the self‐assembly of membraneless compartments (Gomes & Shorter, 2019; Hyman, Weber, & Julicher, 2014). LLPS is a process in which a well‐mixed liquid solution separates into two distinct liquid phases. One phase is enriched in some certain components, and the other is depleted of these components (Alberti & Dormann, 2019). In recent years, an increasing body of evidence has indicated that LLPS plays an important role in cellular organization and the assembly of membraneless organelles, which are comprised of highly concentrated proteins and RNAs (Alberti & Dormann, 2019). In contrast to membrane‐bound organelles, which utilize active transport of molecules across the surrounding membranes to maintain their compositions, the liquid state of the two LLPS phases ensures that the components within these two phases can easily rearrange and can quickly exchange materials with each other. This allows liquid non‐membrane‐bound compartments such as SGs to remain separate from the liquid cytoplasm but able to rapidly respond to environmental stresses. SGs can accomplish this rapid response through entry of macromolecules into the SGs or release of certain components from the SGs (Alberti & Dormann, 2019; Hyman et al., 2014). However, evidence indicates that this process is sensitive to cellular environmental changes such as temperature, pH, and even concentration of molecules (Alberti & Hyman, 2016). High concentrations of macromolecules must reach a critical threshold to start LLPS. However, if a certain concentration is exceeded, macromolecules within the SGs, such as proteins, will tend to form aggregates. This can lead the LLPS‐derived liquid assembly to take on gel‐like or solid‐like properties, which may not function properly (Alberti & Dormann, 2019). Such pathological assemblies, induced by LLPS, are involved in the onset of diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease (Alberti & Dormann, 2019; Falahati & Haji‐Akbari, 2019). The molecules that undergo phase separation include proteins composed of modular interaction domains and intrinsically disordered regions (IDRs). RNA and DNA molecules that harbor multiple interaction regions for binding to other proteins or nucleic acids can also undergo phase separation independently or synergistically with proteins (Jain & Vale, 2017; Molliex et al., 2015). Different kinds of molecular interactions between the diverse regions discussed above can promote LLPS. We have summarized these interactions that promote LLPS and SG formation in Table 1. In the following sections, we mainly focus on the molecular mechanisms underlying SG assembly and discuss the essential factors responsible for the regulation of SG assembly.
Figure 1. Effects of aging on SG assembly, dynamics, and clearance. Formation of SGs begins with nucleation of various RNA‐binding proteins and RNAs. The SGs then grow into larger assemblies via additional protein–protein and protein–RNA interactions. These complexes coalesce into higher‐order SGs in a cytoskeleton system‐dependent manner (a). Aging‐associated mitochondrial dysfunction and inactive metabolism might lead to limited control of this process and aberrant SGs (d). In addition, aging‐associated disease‐causing proteins, misfolded proteins caused by protein homeostasis decline (b), and other chronic stress © during aging lead to impaired SG dynamics and persistent SGs. Aberrant SGs can be cleared by autophagy under normal conditions, but with age, disturbed PQC can have a negative effect on the removal of aberrant SGs (e).
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