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An AKT1-and TRIM21-mediated phosphodegron controls proteasomal degradation of HuR enabling cell survival under heat shock

ABSTRACT: Summary 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/turnover of multiple mRNAs 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. The S100 and E101 residues are required for binding of TRIM21 to HuR. Heat shock-induced phosphorylation of S100 is 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 is required for regulating the cellular level of HuR under heat shock, thereby enabling a crucial adaptive mechanism allowing cell survival in response to heat stress. Graphical abstract Highlights • AKT1-TRIM21 axis controls proteasomal degradation of the RBP HuR under heat shock• TRIM21 recognizes HuR consequent to heat shock-induced phosphorylation of Ser100 of HuR• The kinase AKT1 phosphorylates Ser100 of HuR in response to heat shock• TRIM21-mediated degradation of HuR allows cell survival and recovery from heat shock Genetics; Molecular biology; Cell biology

SUBMITTER: Nag S

PROVIDER: S-EPMC10034463 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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