The involvement of stress granules in aging and aging-associated diseases

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.

Keywords: RNA-binding proteins; aging; aging-associated diseases; nonmembrane assemblies; proteostasis; stress granules.

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 (c) 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)