G3BP1-linked mRNA partitioning supports selective protein synthesis in response to oxidative stress

Abstract

<jats:title>Abstract</jats:title> <jats:p>Cells limit energy-consuming mRNA translation during stress to maintain metabolic homeostasis. Sequestration of mRNAs by RNA binding proteins (RBPs) into RNA granules reduces their translation, but it remains unclear whether RBPs also function in partitioning of specific transcripts to polysomes (PSs) to guide selective translation and stress adaptation in cancer. To study transcript partitioning under cell stress, we catalogued mRNAs enriched in prostate carcinoma PC-3 cell PSs, as defined by polysome fractionation and RNA sequencing (RNAseq), and compared them to mRNAs complexed with the known SG-nucleator protein, G3BP1, as defined by spatially-restricted enzymatic tagging and RNAseq. By comparing these compartments before and after short-term arsenite-induced oxidative stress, we identified three major categories of transcripts, namely those that were G3BP1-associated and PS-depleted, G3BP1-dissociated and PS-enriched, and G3BP1-associated but also PS-enriched. Oxidative stress profoundly altered the partitioning of transcripts between these compartments. Under arsenite stress, G3BP1-associated and PS-depleted transcripts correlated with reduced expression of encoded mitochondrial proteins, PS-enriched transcripts that disassociated from G3BP1 encoded cell cycle and cytoprotective proteins whose expression increased, while transcripts that were both G3BP1-associated and PS-enriched encoded proteins involved in diverse stress response pathways. Therefore, G3BP1 guides transcript partitioning to reprogram mRNA translation and support stress adaptation.</jats:p>

Oxidative stress specifically inhibits replication of dengue virus

“…As our previous report had shown induction of interferon-dependent pathway upon zinc chelation, we speculate that zinc chelation may trigger the cellular antiviral response by employing both the interferon and the oxidative stress responses which affect the ER. --Alternatively, it has been shown that transient induction of oxidative stress leads to partitioning of mRNA transcripts to stress granules leading to selective translation of genes for stress adaptation [35]. Therefore, induction of oxidative stress at early stages of viral infection may disrupt the formation of ER-derived compartments and/or segregation of viral replication complexes from cellular dsRNA sensing machinery thus leading to inhibition of viral replication.…”

Angiogenin (ANG)—Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease

“…Interestingly, both RNH1 and ANG have been detected in the SG core proteome by high throughput approach [ 47 ] ( Figure 1 G). In another study, RNH1 has been detected with G3BP1, a known SG-nucleator protein, in a stress dependent manner [ 48 ]. What is the significance of the presence of RNH1 in the SG is not yet known.…”

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

“…They have all been reported to induce the formation of SGs in vitro [ 4 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. It is surmised that SGs are transient triage centers that are designed to help cells to quickly and transiently modify translation to overcome stress and enhance survival, both of which could be used to escape cancer therapies [ 17 , 18 , 19 ].…”

“…Additionally, SGs sequester untranslated mRNAs concomitantly with the global inhibition of translation [ 17 ]. Some mRNAs, such as chaperone mRNAs, are excluded from the SGs structures, so that they can be preferentially translated during the time of the stress and participate in the proper protein folding and avoid functional defects [ 17 , 19 , 50 ]. By these actions, SGs are described as triage centers for translation of mRNAs during stress exposure [ 17 ].…”

“…By these actions, SGs are described as triage centers for translation of mRNAs during stress exposure [ 17 ]. One leading hypothesis is that SGs are able to reshape translational patterns under stress exposure [ 19 , 51 ].…”