The story of a stressed out cell

Stress is unfortunately a very common word in present days. People say that stress is unavoidable in our current life-style. Well! I am not sure whether the previous statement is completely true; but stress is certainly unavoidable in the life of the cells in our body. Cells can be stressed due to many different reasons. A cell that is starving or injured is under a lot of stress. Toxic chemicals present in the surroundings may cause a cell to become stressed. A cell under stress may either recover from this condition or die as a result of it. In this state, there are proteins that take care of the cell. These proteins stop the cell from making its regular products and start a specialized process that may empower the cell to ride out this crisis.

When under stress, a cell first stops making new proteins from messenger RNA molecules (mRNAs). Elongation factors, molecules that are necessary for protein translation to continue, becomes phosphorylated. This leads to ribosomes, the organelles on which proteins are assembled to fall off the mRNA. Once free, the mRNAs get packaged into clusters called stress granules along with many other proteins like the Tia1, G3BP, FMRP and Ataxin2. As the elongation factors are no longer available to aid in translation, synthesis of protein stops in the entire cell. During this time, only specialized proteins associated with stressful times are synthesized in the cell. One such protein is the master stress-regulator ATF4.But how is the cell able to selectively translate only these specific proteins under stress? We do not know the answer to that question yet.

Proteins associated with times of stress in a cell take care of its damaged DNA, oxidized proteins or ROS (Reactive Oxygen Species), iNOS (inducible Nitric Oxide Synthase). Sometimes, the cell is unable to cope with the stress, then master regulator proteins initiate the program of cell death. When this happens, the cluster of stress granules that had formed within the cell cause the degradation of associated mRNAs. But sometimes, the cell manages to remove the toxic substances causing stress and is able to survive. The stress granules are defused and mRNAs are once again free to be occupied by ribosomes for making new proteins. All of these pathways are together known as the integrated stress response pathways (ISR) of the cell.

Proteins that bind to RNA (RBPs) play an important role during this whole process. Over one thousand RNA binding proteins have been identified in humans. These proteins have specific domains and motifs that help them bind to RNA molecules. There are about 10 different identified domain and motifs, namely; RNA recognition motif, K-homology domain, RGG box, SM domain, DEAD/ DEAH box, Zinc finger motif, dsRNA binding domain, cold shock domain, Pumillo/FBF domain and PAZ domain. RBPs stabilize, modify and process RNA molecules and also aid in their transport.

During stress response RBPs play many important roles like, shut down of global translation, trafficking of mRNAs, protecting t-RNAs, specialized translation, altered splicing and stress granule formation.

According to the work of Ito et al., (JBC, May 1999), PKR-associated protein X or RAX can sense external stimuli of stress and convert into p-RAX, which activates PKR and integrated stress response. ALKBH1 (AlkB homolog 1) is a tRNA demethylase. (Zhou et. al., Molecular Cell, Feb 2018) have shown that during cellular stress ALKBH5 helps in demethylation of ATF4 uORFs (upstream open reading frame). ATF4 is a master regulator of stress related genes. ATF4 mRNA has 2 upstream ORFs, which remains methylated. So, under unstressed condition ATF4 protein synthesis poorly happens. During stressed condition de methylation of these uORFs gives full access of coding region to translation machinery and ATF4 (Activating Transcription Factor 4) protein gets synthesized.

Likewise Dnmt2 (DNA methyl transferase 2) methylates tRNAs during cellular stress and protects them. A18 is a heterogeneous ribonucleoprotein and also an RNA binding protein. A18 comes to cytoplasm during cellular stress (specifically UV radiation) and activates a bunch of stress response genes (Chonglin Yang and France Carrier, JBC, 2001).

Another report suggests that EWS-YB1 helps in altered splicing of MDM2. As a result full length MDM2 protein is synthesized and inhibit P53. Ewing Sarcoma protein EWS binds with another DNA-RNA binging protein YB1 (Y box binding protein 1) and have been found to be altered in several cancers. During cellular stress EWS-YB1 interaction is disrupted and due to altered splicing full length MDM2 does not form. Which leads to P53 activation and cellular apoptosis.

In a nutshell we may conclude that from sensing of stress to protection of mRNAs, t-RNAs and activation of stress response genes or apoptosis, RNA binding proteins are important in almost every step for a profound cellular stress response.

Reference:

The Integrated Stress Response in Lung Disease, Emily F. A. van ’t Wout1,2, Pieter S. Hiemstra1, and Stefan J. Marciniak2; Am J Respir Cell Mol Biol, March 7, 2014, DOI: 10.1165/rcmb.2014-0019TR

The UV-inducible RNA-binding Protein A18 (A18 hnRNP) Plays a Protective Role in the Genotoxic Stress Response; Chonglin Yang and France Carrier, JBC,September 26, 2001, DOI 10.1074/jbc.M105396200

RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage; Matthias Schaefer et al, Genes and Development, 2010, doi/10.1101/gad.586710.

Cells Lacking the Fragile X Mental Retardation Protein (FMRP) have Normal RISC Activity but Exhibit altered Stress Granule Assembly; Marie-Ce´cile Didiot et al, Molecular Biology of the Cell Vol. 19, 428–437, January 1, 2009

The integrated stress response: From mechanism to disease; Mauro Costa-Mattioli and Peter Walter, Science 368, eaat5314 (2020). DOI: 10.1126/science.aat5314

Cotranscriptional exon skipping in the genotoxic stress response; Martin Dutertre et al, Nature Structural and Molecular Biology, 24 October 2010; doi:10.1038/nsmb.1912

RAX, a Cellular Activator for Double-stranded RNA-dependent Protein Kinase during Stress Signaling; Takahiko Ito et al, The Journal of Biological Chemistry, vol. 274, No. 22, Issue of May 28, pp. 15427–15432, 1999

Cotranscriptional exon skipping in the genotoxic stress response; Dutertre et al; Nature Structural & Molecular Biology, 2010

N6 -Methyladenosine Guides mRNA Alternative Translation during Integrated Stress Response; Zhou et al., 2018, Molecular Cell 69, 636–647 February 15, 2018






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