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

Nag, Sharanya; Rahaman, Sayanur; Guha, Abhishek; Ray, Partho Sarothi

doi:10.1016/j.isci.2023.106307

Cited by 3 publications

(5 citation statements)

References 80 publications

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“…Exposure to mild heat shock at 43°C induces HuR degradation, by polyubiquitination of the Lys182 residue, which is also found to be ubiquitinated by the E3 ubiquitin ligase TRIM21 upon UV irradiation (Abdelmohsen et al, 2009; Guha et al, 2019). TRIM21 also polyubiquitinates the Lys182 residue in HuR upon exposure to heat shock, leading to its degradation (Nag et al, 2023) (Figure 2d). TRIM21‐mediated degradation of HuR enhances cell viability and adaptation to heat shock.…”

Section: Heat Shock Regulates Phosphorylation and Degradation Of Hurmentioning

confidence: 99%

“…Two amino acid residues in the linker domain joining RRMs 1 and 2 of HuR, Ser100, and Glu101, have been identified as primary determinants for the interaction between TRIM21 and HuR under heat shock. Moreover, phosphorylation of the Ser100 residue is necessary for interaction of TRIM21 with HuR and its subsequent degradation (Nag et al, 2023). It is likely that phosphorylated Ser100, together with the adjacent Glu101 residue, generates an acidic patch in the flexible linker region allowing recognition by TRIM21.…”

Section: Heat Shock Regulates Phosphorylation and Degradation Of Hurmentioning

confidence: 99%

“…The caspase‐mediated cleavage of HuR in response to apoptotic stimuli has been suggested to switch its function from being a pro‐survival factor under normal conditions to becoming a promoter of apoptosis under lethal stress, as the HuR cleavage products selectively bind to and stabilize the mRNA encoding caspase‐9, a pro‐apoptotic factor (von Roretz et al, 2013). The plethora of PTMs of HuR raises the interesting possibility that different combinations of PTMs might cause the observed switch of HuR from being an anti‐apoptotic and pro‐proliferative factor in various cancers (Abdelmohsen & Gorospe, 2010) to a pro‐apoptotic and anti‐proliferative factor upon exposure to multiple stress conditions (Ahuja et al, 2016; Nag et al, 2023; Poria et al, 2016). The nature and intensity of the stress stimuli causing alterations in the PTMs of HuR, and the resultant changes in its binding specificities to target mRNAs, might be a possible cause of this phenomenon.…”

Section: Regulation Of Hur By Post‐translational Modificationsmentioning

confidence: 99%

“…Therefore, sequential phosphorylation by AKT1 at S100 and ubiquitination by TRIM21 at K182 determine a novel “phosphodegron” in HuR that regulates the cellular level of HuR under heat shock (Figure 2d). The transient reduction in HuR level in cells regulates the stability of multiple stress‐responsive HuR target mRNAs, enabling a crucial adaptive mechanism allowing cell survival in response to heat stress (Nag et al, 2023).…”

Section: Heat Shock Regulates Phosphorylation and Degradation Of Hurmentioning

confidence: 99%

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Fates and functions of RNA‐binding proteins under stress

Goswami,

Nag,

Ray

2023

WIREs RNA

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Exposure to stress activates a well‐orchestrated set of changes in gene expression programs that allow the cell to cope with and adapt to the stress, or undergo programmed cell death. RNA–protein interactions, mediating all aspects of post‐transcriptional regulation of gene expression, play crucial roles in cellular stress responses. RNA‐binding proteins (RBPs), which interact with sequence/structural elements in RNAs to control the steps of RNA metabolism, have therefore emerged as central regulators of post‐transcriptional responses to stress. Following exposure to a variety of stresses, the dynamic alterations in the RNA‐protein interactome enable cells to respond to intracellular or extracellular perturbations by causing changes in mRNA splicing, polyadenylation, stability, translation, and localization. As RBPs play a central role in determining the cellular proteome both qualitatively and quantitatively, it has become increasingly evident that their abundance, availability, and functions are also highly regulated in response to stress. Exposure to stress initiates a series of signaling cascades that converge on post‐translational modifications (PTMs) of RBPs, resulting in changes in their subcellular localization, association with stress granules, extracellular export, proteasomal degradation, and RNA‐binding activities. These alterations in the fate and function of RBPs directly impact their post‐transcriptional regulatory roles in cells under stress. Adopting the ubiquitous RBP HuR as a prototype, three scenarios illustrating the changes in nuclear‐cytoplasmic localization, RNA‐binding activity, export and degradation of HuR in response to inflammation, genotoxic stress, and heat shock depict the complex and interlinked regulatory mechanisms that control the fate and functions of RBPs under stress.This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications

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Section: Heat Shock Regulates Phosphorylation and Degradation Of Hurmentioning

confidence: 99%

Section: Heat Shock Regulates Phosphorylation and Degradation Of Hurmentioning

confidence: 99%

Section: Regulation Of Hur By Post‐translational Modificationsmentioning

confidence: 99%

Section: Heat Shock Regulates Phosphorylation and Degradation Of Hurmentioning

confidence: 99%

See 2 more Smart Citations

Fates and functions of RNA‐binding proteins under stress

Goswami,

Nag,

Ray

2023

WIREs RNA

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“…In addition to that, depletion of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and inhibitor of nuclear factor-kB kinase (IKK) proteins in primary human cells (human macrophages) was also reported that led to the functional alterations in macrophages and reduced their production of pro-inflammatory cytokines, such as IL-1ꞵ. Lately, Nag et al [ 80 ] elaborated an unidentified role of TRIM-21 in regulating human antigen R (HuR), an RNA-binding protein, required for regulating cell survival under stress conditions. The authors found that under heat-shock conditions AKT1 phosphorylates HuR at the K182 position, priming it for TRIM-21 mediated ubiquitination.…”

Section: Trim-awaymentioning

confidence: 99%

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

Joshi,

Dey,

2023

Exploration of Targeted Anti-Tumor Therapy

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A generalized therapeutic strategy for various disease conditions, including cancer, is to deplete or inactivate harmful protein targets. Various forms of protein or gene silencing molecules, e.g., small molecule inhibitors, RNA interference (RNAi), and microRNAs (miRNAs) have been used against druggable targets. Over the past few years, targeted protein degradation (TPD) approaches have been developed for direct degradation of candidate proteins. Among the TPD approaches, proteolysis targeting chimeras (PROTACs) have emerged as one of the most promising approaches for the selective elimination of proteins via the ubiquitin-proteasome system. Other than PROTACs, TPD methods with potential therapeutic use include intrabody-mediated protein knockdown and tripartite motif-21 (TRIM-21) mediated TRIM-Away. In this review, protein knockdown approaches, their modes of action, and their advantages over conventional gene knockdown approaches are summarized. In cancers, disease-associated protein functions are often executed by specific post-translational modifications (PTMs). The role of TRIM-Away is highlighted in the direct knockdown of PTM forms of target proteins. Moreover, the application challenges and the prospective clinical use of TPD approaches in various diseases are also discussed.

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The essential roles of lncRNAs/PI3K/AKT axis in gastrointestinal tumors

Li,

Ma,

2024

Front. Cell Dev. Biol.

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The role of long noncoding RNA (lncRNA) in tumors, particularly in gastrointestinal tumors, has gained significant attention. Accumulating evidence underscores the interaction between various lncRNAs and diverse molecular pathways involved in cancer progression. One such pivotal pathway is the PI3K/AKT pathway, which serves as a crucial intracellular mechanism maintaining the balance among various cellular physiological processes for normal cell growth and survival. Frequent dysregulation of the PI3K/AKT pathway in cancer, along with aberrant activation, plays a critical role in driving tumorigenesis. LncRNAs modulate the PI3K/AKT signaling pathway through diverse mechanisms, primarily by acting as competing endogenous RNA to regulate miRNA expression and associated genes. This interaction significantly influences fundamental biological behaviors such as cell proliferation, metastasis, and drug resistance. Abnormal expression of numerous lncRNAs in gastrointestinal tumors often correlates with clinical outcomes and pathological features in patients with cancer. Additionally, these lncRNAs influence the sensitivity of tumor cells to chemotherapy in multiple types of gastrointestinal tumors through the abnormal activation of the PI3K/AKT pathway. These findings provide valuable insights into the mechanisms underlying gastrointestinal tumors and potential therapeutic targets. However, gastrointestinal tumors remain a significant global health concern, with increasing incidence and mortality rates of gastrointestinal tumors over recent decades. This review provides a comprehensive summary of the latest research on the interactions of lncRNA and the PI3K/AKT pathway in gastrointestinal tumor development. Additionally, it focuses on the functions of lncRNAs and the PI3K/AKT pathway in carcinogenesis, exploring expression profiles, clinicopathological characteristics, interaction mechanisms with the PI3K/AKT pathway, and potential clinical applications.

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

Cited by 3 publications

References 80 publications

Fates and functions of RNA‐binding proteins under stress

Fates and functions of RNA‐binding proteins under stress

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

The essential roles of lncRNAs/PI3K/AKT axis in gastrointestinal tumors

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