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. Author manuscript; available in PMC: 2024 Sep 2.
Published in final edited form as: Biochem Soc Trans. 2022 Dec 16;50(6):1715–1724. doi: 10.1042/BST20220549

Figure 1. Proposed mechanisms by which stress granules and the RQC pathway intersect.

Figure 1.

(A) Overview of the RQC and saRQC pathways. In the RQC, translation of aberrant mRNAs induces ribosome stalling and collisions that are recognized by ZNF598, triggering ribosome splitting [32]. NEMF then recognizes the 60S ribosomal subunit and catalyzes the addition of carboxy-terminal alanine threonine (‘CAT tails’) onto the nascent peptide [33]. NEMF also stabilizes LTN1 which adds ubiquitin to the nascent chain [14]. The ubiquitinated nascent chain is extracted from the 60S ribosome by VCP and unfolded for proteasome- mediated degradation [29]. In the saRQC, VCP, NEMF, and LTN1 may aid in the partitioning of specific RNAs to SGs following arsenite or heat stress [20]. (B) Ribosome stalling and collisions activate the ISR through GCN2. GCN2 dimerizes, autophosphorylates, and phosphorylates eIF2α to trigger the ISR and potentially cause SG formation in a mechanism that may depend on GCN1 and GCN20. (C) Storage and recycling of the 40S ribosomal subunit is mediated by G3BP1. Upon ribosome collisions, ZNF598 ubiquitinates the 40S ribosomal subunit [34] which can in turn be recognized and removed by G3BP1-family-USP10 to recycle the 40S subunit for another round of translation [25]. In stress conditions such as arsenite, clotrimazole (CZ), and pateamine A (Pat A), 40S subunit proteins co-localize with SGs [35]. When G3BP1 associates with the cytoplasmic activated/proliferation-associated protein 1 (Caprin1), SG formation is promoted. In contrast, when G3BP1 associates with USP10, SG formation is inhibited [35]. (D) Roles of RQC factors in SG assembly and disassembly. In response to environmental and cell intrinsic stressors, eIF2α can be phosphorylated thus limiting ternary complex production to suppress translation initiation [2]. This in turn leads to the formation of SGs that are composed of various RBPs, 40S subunit proteins, and RNAs. SGs can be cleared by autophagy [19] or ubiquitination and degradation of the SG protein G3BP1 in stress-specific contexts [7].