Role of Proteostasis Regulation in the Turnover of Stress Granules

Abstract

RNA-binding proteins (RBPs) and RNAs can form dynamic, liquid droplet-like cytoplasmic condensates, known as stress granules (SGs), in response to a variety of cellular stresses. This process is driven by liquid–liquid phase separation, mediated by multivalent interactions between RBPs and RNAs. The formation of SGs allows a temporary suspension of certain cellular activities such as translation of unnecessary proteins. Meanwhile, non-translating mRNAs may also be sequestered and stalled. Upon stress removal, SGs are disassembled to resume the suspended biological processes and restore the normal cell functions. Prolonged stress and disease-causal mutations in SG-associated RBPs can cause the formation of aberrant SGs and/or impair SG disassembly, consequently raising the risk of pathological protein aggregation. The machinery maintaining protein homeostasis (proteostasis) includes molecular chaperones and co-chaperones, the ubiquitin-proteasome system, autophagy, and other components, and participates in the regulation of SG metabolism. Recently, proteostasis has been identified as a major regulator of SG turnover. Here, we summarize new findings on the specific functions of the proteostasis machinery in regulating SG disassembly and clearance, discuss the pathological and clinical implications of SG turnover in neurodegenerative disorders, and point to the unresolved issues that warrant future exploration.

Cell-Free Analysis Reveals the Role of RG/RGG Motifs in DDX3X Phase Separation and Their Potential Link to Cancer Pathogenesis

“…Our proposed interaction mechanism suggests that DDX3X and G3BP1 may interact through their RG/RGG domains and subsequently bind to translation factors eIF4A/E/G to form stress granules (Figure 7B) [33,39,40]. These stress granules associate with mRNA and regulate the translation of downstream genes by influencing the function of the 43S preinitiation complex (PIC), ultimately affecting cellular physiological functions [41][42][43]. Targeting the interaction between DDX3X and G3BP1, or their individual phase separation properties, may represent a potential therapeutic strategy for cancers in which these proteins are dysregulated.…”

Stress granules in cancer: Adaptive dynamics and therapeutic implications

“… 32 Other factors such as pH changes, proteasomal degradation machinery, and modulation of specific PTM (like phosphorylation, ubiquitination, and SUMOylation) also influence SG dynamics and turnover. 59 , 60 , 61 SGs can act as buffers for the ubiquitin-proteasome system, potentially preventing proteotoxic stress in the nucleus by sequestering damaged proteins and facilitating their eventual disposal. SG disassembly can be regulated by the involvement of specific adaptor proteins like ZFAND1, ATPases like VCP/p97, and enzymes like deubiquitinating enzymes (DUBs) that remove ubiquitin moieties from granule components.…”

The <italic>pros</italic> and <italic>cons</italic> of ubiquitination on the formation of protein condensates

“…The two DUBs have different preferences for Ub substrates: USP13 generally hydrolyzes protein-conjugated polyUb chains, whereas USP5 hydrolyzes unanchored polyUb chains [ 87 , 109 – 113 ] . General discussion of ubiquitination in regulating SG dynamics can also be found in published reviews [ 7 , 94 , 114 ] .…”