Since 2020, the COVID-19 pandemic has devastated human civilization throughout the earth. The pandemic is returning in different waves because of constant changes in the genetic components of the virus. Had we been able to predict the nature and timing of these waves earlier, numerous lives could, in essence, have been saved. It is evident that the situation has spiraled out of control in several countries for want of proper preventive measures. In this article, we described a comprehensive mathematical approach to understand the nature of the pandemic waves. Also, we determined the probable timing of the third wave that will help the concerned government(s) to take the necessary steps to better prepare for the unforeseen situation.
Post-transcriptional regulation by RNA-binding proteins (RBPs) is a major mode of controlling gene expression under stress conditions. The RBP HuR regulates the translation and/or stability of mRNAs of multiple genes involved in stress responses. HuR is degraded in response to heat stress consequent to ubiquitination of the K182 amino acid residue. We have identified TRIM21 as the E3-ubiquitin ligase causing HuR polyubiquitination at K182 and proteasomal degradation under heat shock. TRIM21-mediated degradation of HuR protected cells from heat-shock induced cell death. By a combination of molecular dynamics simulation and experimentation we found the S100 and E101 residues to be required for binding of TRIM21 to HuR. Heat shock-induced phosphorylation of S100 was necessary for TRIM21 interaction with HuR and subsequent degradation. We identified AKT1 as the kinase which phosphorylates S100, allowing the recognition of HuR by TRIM21. Sequential phosphorylation by AKT1 and ubiquitination by TRIM21 therefore determine a “phosphodegron” in HuR that regulates the cellular level of HuR under heat shock, thereby enabling a crucial adaptive mechanism allowing cell survival in response to heat stress.
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