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Changing faces of stress: Impact of heat and arsenite treatment on the composition of stress granules

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Abstract Stress granules (SGs), hallmarks of the cellular adaptation to stress, promote survival, conserve cellular energy, and are fully dissolved upon the cessation of stress treatment. Different stresses can initiate the assembly of SGs, but arsenite and heat are the best studied of these stresses. The composition of SGs and posttranslational modifications of SG proteins differ depending on the type and severity of the stress insult, methodology used, cell line, and presence of overexpressed and tagged proteins. A group of 18 proteins showing differential localization to SGs in heat‐ and arsenite‐stressed mammalian cell lines is described. Upon severe and prolonged stress, physiological SGs transform into more solid protein aggregates that are no longer reversible and do not contain mRNA. Similar pathological inclusions are hallmarks of neurodegenerative diseases. SGs induced by heat stress are less dynamic than SGs induced by arsenite and contain a set of unique proteins and linkage‐specific polyubiquitinated proteins. The same types of ubiquitin linkages have been found to contribute to the development of neurodegenerative disorders such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS). We propose heat stress‐induced SGs as a possible model of an intermediate stage along the transition from dynamic, fully reversible arsenite stress‐induced SGs toward aberrant SGs, the hallmark of neurodegenerative diseases. Stress‐ and methodology‐specific differences in the compositions of SGs and the transition of SGs to aberrant protein aggregates are discussed. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Export and Localization > RNA Localization
U2OS FLP‐IN cells stably expressing GFP‐eIF4E2 were stressed by sodium arsenite or heat for 1 hr. In the latter case, the temperature was measured directly via a submersible thermometer probe on the glass coverslip, essentially as described in Frydryskova et al. (2016). Lower temperatures determined for stress induction correspond to the method of direct temperature control at the cover slip. Heat stress causes SGs formation only in a limited temperature window (Frydryskova et al., 2016). Lethal doses of sodium arsenite (N. L. Kedersha et al., 1999) induce SG fusion and swelling. Under severe acute heat stress, SGs and PBs fuse and form large SG‐PB aggregates (highlighted with arrows). SG marker—mouse anti‐eIF3B, SC‐137214, Santa Cruz, diluted 1:500; PB marker—rabbit anti‐DDX6, A300‐461A, Bethyl Laboratories, diluted 1:500. Similar results were also obtained in wt U2OS cells with Dcp1, a marker of PBs. Pictures were taken using a wide‐field Olympus ScanR microscope, and the scale bars represent 20 μm
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The red circle shows an assembly of heat stress‐specific signal transduction pathway components: focal adhesion kinase (FAK), Ubiquitin specific peptidase 5 (USP5), Ubiquitin specific peptidase 13 (USP13), and Protein kinase Cα (PKCα). Members of signal transduction pathways that localize to SGs induced under both arsenite and heat stress conditions are contained within the orange circle: Mammalian target of rapamycin (mTOR) is depicted in italics because its localization in heat stress‐induced SG was tested only in yeast, the mTOR downstream kinases ribosomal protein S6 kinase I (S6K1) and II (S6K2), the mTORC1 components Astrin and Raptor, Growth factor receptor bound protein 7 (GRB7), TNF receptor‐associated factor 2 (TRAF2), TAR DNA‐binding protein (TDP‐43), receptor for activated C kinase 1 (RACK1), Ras homolog gene family member A (RhoA), Rho‐associated coiled‐coil‐containing protein kinase 1 (ROCK1), poly(ADP‐ribose) polymerase (PARP), Jumonji C (JmjC) domain‐containing protein 6 (JMJD6), Histone deacetylase 6 (HDAC6), and Ubiquitin‐specific peptidase 10 (USP10). The yellow circle contains signal transduction pathway members specific to arsenite stress‐induced SGs: SMAUG (SMG‐1) and protein arginine methyltransferase (PRMT1). The following members of signaling pathways are thought to be enriched in arsenite‐induced SGs, but to the best of our knowledge, their localization in SGs induced under heat stress has never been tested: the E3 ubiquitin ligase Roquin, Disheveled (DVL), 2‐oxoglutarate and iron‐dependent oxygenase domain‐containing 1g (OGFOD1), dual specificity tyrosine phosphorylation‐regulated kinase (DYRK3), protein kinase SYK (SYK), angiogenin (ANG), 5´AMP‐activated protein kinase alpha (AMPKα2), casein kinase 2 (CK‐2), ribosomal S6 kinase A3 (RSK‐2), NEDD8‐conjugating enzyme Ubc12 (UBE2M), neural precursor cell expressed developmentally down‐regulated protein 8 (NEDD8), and poly(ADP‐ribose) glycohydrolase (PARG). Proteins within two circles in the figure play a stress‐specific biochemical role but are localized to SGs induced under both conditions. The rationale for classifying PKCα and FAK as heat stress SG‐specific molecules and SMG‐1 and PRMT‐1 as arsenite stress SG‐specific molecules is discussed in the text. AS—arsenite stress, HS—heat shock
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RNA in Disease and Development > RNA in Disease
RNA Export and Localization > RNA Localization
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

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