Chronic starvation induces non-canonical pro-death stress granules

Abstract

Stress granules (SGs) assemble under stress-induced conditions that inhibit protein synthesis, including phosphorylation of eIF2α, inhibition of the RNA helicase eIF4a proteins or inactivation of mTORC1. Classically defined SGs are composed of translation initiation factors, 40S ribosomes, RNA-binding proteins and poly(A) mRNAs. As such, they represent an important compartment for storage of mRNAs and regulation of their translation. Emerging work on SGs indicates that these structures might promote cellular survival in diverse disease states. Yet, much work on SG formation and function employs acute stress conditions, which might not accurately reflect the chronic stresses that manifest in human disease. Here, we used prolonged nutrient starvation to model and investigate SG formation and function during chronic stress in a human cell line and mouse embryonic fibroblasts. Surprisingly, we found that SGs that form under chronic nutrient starvation lack 40S ribosomes, do not actively exchange their constituent components with cytoplasmic pools and promote cell death. We named these SGs starvation-induced SGs (stSGs). Our results on stSGs imply that SG assembly and function in the context of prolonged nutrient starvation stress differ significantly from what has been described for acute stress conditions.

AMPK‐mediated formation of stress granules is required for dietary restriction‐induced longevity in Caenorhabditis elegans

“…However, TIAR‐1 granules exist mainly in the intestine, whereas GTBP‐1 granules could be found in most of the tissues. The differences in the tissue distribution of these two proteins have supported the idea that SGs may have different subtypes (Panas, Ivanov, & Anderson, 2016; Reineke, Cheema, Dubrulle, & Neilson, 2018). Interestingly, we found that tiar‐1 knockdown significantly inhibited the heat‐induced GTBP‐1 granule formation in all tissues, while TIAR‐1 foci could mostly be found in the intestine.…”

Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics

“…Evidence for an important role of phosphorylation in the regulation of RNP granule dynamics mainly comes from the observation that inhibition or overexpression of certain kinases leads to altered RNP granule assembly or disassembly (117)(118)(119)(120)(121). In many cases, the involved substrate(s) and underlying molecular mechanisms are still unclear, but there are a few examples from which we can learn about possible mechanisms regarding how phosphorylation may modulate RNP granules: (a) by modulating LLPS of certain RBPs, thus promoting their condensation or decondensation and hence RNP granule assembly or disassembly, and (b) by promoting degradation of certain RBPs (by the proteasome or autophagy), hence reducing their cellular concentration and altering RNP granule assembly or disassembly (Fig.…”

“…Besides DYRK3, casein kinase 2 (CK2) was recently found to cause SG disassembly, most likely via phosphorylation of the SG-nucleating protein G3BP1 (119). It has long been known that phosphorylation of G3BP1 on Ser-149 regulates the protein's oligomerization, SG recruitment, and RNase activity (123,124), but only recently was CK2 identified as the kinase that phosphorylates G3BP1 on Ser-149 and thus promotes SG disassembly (119). Whether CK2 also acts on other key SG regulators, such as other SG nucleating RBPs or translation inhibition factors, and hence affects SG dynamics through multiple different mechanisms remains to be examined.…”

“…RBPs are frequently both methylated and phosphorylated, suggesting that they could cooperate or interfere with one another. For instance, for the SG nucleating protein G3BP1, it has been proposed that demethylation may cooperate with dephosphorylation to promote SG assembly and translational inhibition (52,119). Other examples could include FUS or hnRNP-A1, which are constitutively Arg-methylated and become phosphorylated during DNA damage, oxidative stress, or heat stress, respectively (22,135).…”

Class I HDAC inhibitors enhance YB ‐1 acetylation and oxidative stress to block sarcoma metastasis

“…Other potential pro‐metastatic functions include roles in stabilizing oncogenic transcripts , binding of tRNA fragments to mediate cytoprotective oxidative stress‐induced translational repression , and translational activation of the Rho GTPAse‐dependent ROCK1 ser/thr kinase to increase cell motility . We also found that in sarcomas, YB‐1 binds and activates mRNA encoding Ras‐GTPase‐activating protein (SH3 domain) binding protein 1 (G3BP1), a key stress granule (SG) nucleating protein . SGs, mainly studied under oxidative stress, are cytoplasmic aggregates composed of RBPs, the 40S ribosome, stalled translation initiation complexes, and silenced mRNAs that form rapidly under cell stress, and recent studies have begun to uncover the composition of these structures .…”