stress granules
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2022 ◽  
Author(s):  
Giulia Ada Corbet ◽  
James M Burke ◽  
Gaia Rachel Bublitz ◽  
Roy Parker

Mammalian cells respond to dsRNA in multiple manners. One key response to dsRNA is the activation of PKR, an eIF2α kinase, which triggers translational arrest and the formation of stress granules. However, the process of PKR activation in cells is not fully understood. In response to increased endogenous or exogenous dsRNA, we observed that PKR forms novel cytosolic condensates, referred to as dsRNA-induced foci (dRIFs). dRIFs contain dsRNA, form in proportion to dsRNA, and are enhanced by longer dsRNAs. dRIFs also enrich several other dsRNA-binding proteins including ADAR1, Stau1, NLRP1, and PACT. Strikingly, dRIFs correlate with and form prior to translation repression by PKR and localize to regions of cells where PKR activation is initiated. We suggest that dRIF formation is a mechanism cells utilize to enhance the sensitivity of PKR activation in response to low levels of dsRNA, or to overcome viral inhibitors of PKR activation.


2022 ◽  
Vol 12 ◽  
Author(s):  
Ritesh Kumar Srivastava ◽  
Bharat Mishra ◽  
Suhail Muzaffar ◽  
Marina S. Gorbatyuk ◽  
Anupam Agarwal ◽  
...  

The use of chemical warfare agents is prohibited but they have been used in recent Middle Eastern conflicts. Their accidental exposure (e.g. arsenical lewisite) is also known and causes extensive painful cutaneous injury. However, their molecular pathogenesis is not understood. Here, we demonstrate that a nexus of stress granules (SGs), integrated stress, and RNA binding proteins (RBPs) Roquin and Reganse-1 play a key role. Lewisite and its prototype phenylarsine oxide (PAO) induce SG assembly in skin keratinocytes soon after exposure, which associate with various RBPs and translation-related proteins. SG disassembly was detected several hours after exposure. The dynamics of SG assembly-disassembly associates with the chemical insult and cell damage. Enhanced Roquin and Regnase-1 expression occurs when Roquin was recruited to SGs and Regnase-1 to the ribosome while in the disassembling SGs their expression is decreased with consequent induction of inflammatory mediators. SG-targeted protein translational control is regulated by the phosphorylation-dependent activation of eukaryotic initiation factors 2α (eIF2α). Treatment with integrated stress response inhibitor (ISRIB), which blocks eIF2α phosphorylation, impacted SG assembly dynamics. Topical application of ISRIB attenuated the inflammation and tissue disruption in PAO-challenged mice. Thus, the dynamic regulation of these pathways provides underpinning to cutaneous injury and identify translational therapeutic approach for these and similar debilitating chemicals.


2022 ◽  
Vol 145 ◽  
pp. 112382
Author(s):  
Paulina Pietras ◽  
Anaïs Aulas ◽  
Marta M. Fay ◽  
Marta Leśniczak-Staszak ◽  
Mateusz Sowiński ◽  
...  

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanan Liu ◽  
Shijie Liu ◽  
Huiying Shi ◽  
Jingyue Ma ◽  
Meng Jing ◽  
...  

Tudor staphylococcal nucleases (TSNs) are evolutionarily conserved RNA binding proteins, which include redundant TSN1 and TSN2 in Arabidopsis. It has been showed TSNs are the components of stress granules (SGs) and regulate plant growth under salt stress. In this study, we find a binding protein of TSN1, RH31, which is a DEAD-box RNA helicase (RH). Subcellular localization studies show that RH31 is mainly located in the nucleus, but under salinity, it translocates to the cytoplasm where it accumulates in cytoplasmic granules. After cycloheximide (CHX) treatment which can block the formation of SGs by interfering with mRNP homeostasis, these cytoplasmic granules disappeared. More importantly, RH31 co-localizes with SGs marker protein RBP47. RH31 deletion results in salt-hypersensitive phenotype, while RH31 overexpression causes more resistant to salt stress. In summary, we demonstrate that RH31, the TSN1 binding protein, is a component of plant SGs and participates in regulation of salt-stress tolerance in Arabidopsis.


Author(s):  
Benjamin L. Zaepfel ◽  
Jeffrey D. Rothstein

Stress granule formation is a complex and rapidly evolving process that significantly disrupts cellular metabolism in response to a variety of cellular stressors. Recently, it has become evident that different chemical stressors lead to the formation of compositionally distinct stress granules. However, it is unclear which proteins are required for the formation of stress granules under different conditions. In addition, the effect of various stressors on polyadenylated RNA metabolism remains enigmatic. Here, we demonstrate that G3BP1/2, which are common stress granule components, are not required for the formation of stress granules specifically during osmotic stress induced by sorbitol and related polyols. Furthermore, sorbitol-induced osmotic stress leads to significant depletion of nuclear polyadenylated RNA, a process that we demonstrate is dependent on active mRNA export, as well as cytoplasmic and subnuclear shifts in the presence of many nuclear RNA-binding proteins. We assessed the function of multiple shifted RBPs and found that hnRNP U, but not TDP-43 or hnRNP I, exhibit reduced function following this cytoplasmic shift. Finally, we observe that multiple stress pathways lead to a significant reduction in transcription, providing a possible explanation for our inability to observe loss of TDP-43 or hnRNP I function. Overall, we identify unique outcomes following osmotic stress that provide important insight into the regulation of RNA-binding protein localization and function.


2021 ◽  
pp. 105585
Author(s):  
Haiyan An ◽  
Gioana Litscher ◽  
Naruaki Watanabe ◽  
Wenbin Wei ◽  
Tadafumi Hashimoto ◽  
...  

2021 ◽  
Author(s):  
Ilya Shabanov ◽  
J. Ross Buchan

Quantification of cellular structures in fluorescence microscopy data is a key means of understanding cellular function. Unfortunately, numerous cellular structures present unique challenges in their ability to be unbiasedly and accurately detected and quantified. In our studies on stress granules in yeast, users displayed a striking variation of up to 3.7-fold in foci calls and were only able to replicate their results with 62-78% correlation, when requantifying the same images. To facilitate consistent results we developed HARLEY (Human Augmented Recognition of LLPS Ensembles in Yeast), a customizable software for detection and quantification of stress granules in S.cerevisiae. After a brief model training on ~20 cells the detection of foci is fully automated and based on closed loops in intensity contours, constrained only by the a-priori known size of the features of interest. Since no shape is implied, this method is not limited to round features, as is often the case with other algorithms. Candidate features are annotated with a set of geometrical and intensity-based properties to train a kernel Support Vector Machine to recognize features of interest. The trained classifier is then used to create consistent results across datasets. HARLEY is aimed at users without technical expertise, allows for batch processing and is freely available, which should be of broad interest to users focused on analysis of microscopy data in yeast.


iScience ◽  
2021 ◽  
pp. 103562
Author(s):  
Syed Nabeel-Shah ◽  
Hyunmin Lee ◽  
Nujhat Ahmed ◽  
Giovanni L. Burke ◽  
Shaghayegh Farhangmehr ◽  
...  

Author(s):  
Nirnay Samanta ◽  
Sara S. Ribeiro ◽  
Mailin Becker ◽  
Emeline Laborie ◽  
Roland Pollak ◽  
...  
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