Ubiquitin-mediated proteolysis of HuR by heat shock

Abdelmohsen, Kotb; Srikantan, Subramanya; Yang, Xiaoling; Lal, Ashish; Kim, Hyeon Ho; Kuwano, Yuki; Galbán, Stefanie; Becker, Kevin G.; Kamara, Davida; Cabo, Rafael de; Gorospe, Myriam

doi:10.1038/emboj.2009.67

Cited by 153 publications

(160 citation statements)

References 56 publications

(84 reference statements)

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“…On the basis of an increasing literature establishing a correlation between posttranslational modifications of RBPs and acquisition of new biological properties (22), we next compared HuR phosphorylation status between ALK þ and ALK À cells. Indeed, besides methylation and ubiquitinylation (27,28), HuR has been shown to be phosphorylated on serine and threonine residues in response to proliferation signals or damaging stimuli (26). Thus, phosphorylation of HuR by the serine-threonine kinases cdk1, PKCd, or pKCa has been reported to induce HuR translocation into the cytoplasm and modulate its RNA-binding properties (26).…”

Section: Discussionmentioning

confidence: 99%

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

Bergalet

Fawal

Lopez

et al. 2011

Molecular Cancer Research

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The CCAAT/enhancer-binding protein b (C/EBPb) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK þ ). Although ALK-mediated C/EBPb transcriptional activation has been reported, C/EBPb mRNA possesses U-and AU-rich domains in its 3 0 -untranslated region (3 0 -UTR) that might be privileged targets for posttranscriptional control in ALK þ ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3 0

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Section: Discussionmentioning

confidence: 99%

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

Bergalet

Fawal

Lopez

et al. 2011

Molecular Cancer Research

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“…For instance, ubiquitination infl uences the stability of HuR, which is degraded by the ubiquitin-proteasome pathway following a moderate heat shock (95) . Certain classes of RBPsprimarily hnRNPs and serine/arginine-rich (SR) proteins -are site-specifi cally methylated by arginine methy ltransferases (PRMTs) [reviewed in (96) ].…”

Section: Dynamics -Rewiring the Rna-protein Networkmentioning

confidence: 99%

RNA regulons and the RNA-protein interaction network

Imig¹,

Kanitz²,

Gerber

2012

BioMolecular Concepts

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The development of genome-wide analysis tools has prompted global investigation of the gene expression program, revealing highly coordinated control mechanisms that ensure proper spatiotemporal activity of a cell ' s macromolecular components. With respect to the regulation of RNA transcripts, the concept of RNA regulons, which -by analogy with DNA regulons in bacteria -refers to the coordinated control of functionally related RNA molecules, has emerged as a unifying theory that describes the logic of regulatory RNA-protein interactions in eukaryotes. Hundreds of RNA-binding proteins and small non-coding RNAs, such as microRNAs, bind to distinct elements in target RNAs, thereby exerting specifi c and concerted control over posttranscriptional events. In this review, we discuss recent reports committed to systematically explore the RNA-protein interaction network and outline some of the principles and recurring features of RNA regulons: the coordination of functionally related mRNAs through RNAbinding proteins or non-coding RNAs, the modular structure of its components, and the dynamic rewiring of RNA-protein interactions upon exposure to internal or external stimuli. We also summarize evidence for robust combinatorial control of mRNAs, which could determine the ultimate fate of each mRNA molecule in a cell. Finally, the compilation and integration of global protein-RNA interaction data has yielded fi rst insights into network structures and provided the hypothesis that RNA regulons may, in part, constitute noise ' buffers ' to handle stochasticity in cellular transcription.

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“…It has been demonstrated that phosphorylation at specific serines or a threonine of HuR can lead to altered cellular localization of the protein and, in one case, can increase the RNA-binding affinity of HuR (Doller et al 2010;Srikantan and Gorospe 2012). One report indicated that heat shock induces ubiquitination of HuR at Lys 182, leading to degradation of HuR and decreased levels of HuR target mRNA abundance (Abdelmohsen et al 2009). The HuR proteins have been shown to interact dynamically with their RNA targets in various large mRNPs (Keene 2001;Mukherjee et al 2009;Masuda et al 2011).…”

mentioning

confidence: 99%

The p97–UBXD8 complex destabilizes mRNA by promoting release of ubiquitinated HuR from mRNP

Zhou

Geng²,

Luo³

et al. 2013

Genes Dev.

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The assembly and disassembly of ribonucleoproteins (RNPs) are dynamic processes that control every step of RNA metabolism, including mRNA stability. However, our knowledge of how RNP remodeling is achieved is largely limited to RNA helicase functions. Here, we report a previously unknown mechanism that implicates the ATPase p97, a protein-remodeling machine, in the dynamic regulation of mRNP disassembly. We found that p97 and its cofactor, UBXD8, destabilize p21, MKP-1, and SIRT1, three established mRNA targets of the RNA-binding protein HuR, by promoting release of HuR from mRNA. Importantly, ubiquitination of HuR with a short K29 chain serves as the signal for release. When cells are subjected to stress conditions, the steady-state levels of HuR ubiquitination change, suggesting a new mechanism through which HuR mediates the stress response. Our studies reveal a new paradigm in RNA biology: nondegradative ubiquitin signaling-dependent disassembly of mRNP promoted by the p97-UBXD8 complex to control mRNA stability.[Keywords: HuR; mRNA stability; ubiquitin] Supplemental material is available for this article. RNA-binding proteins (RBPs) recognize specific cis-regulatory mRNA elements to form ribonucleoprotein (RNP) complexes, which control every aspect of the life of a mRNA from pre-mRNA processing to mRNA localization, translation, and turnover (Moore 2005;Keene 2007). A different array of proteins is loaded onto pre-mRNA/ mRNA during every step of post-transcriptional mRNA metabolism, making assembly and disassembly of mRNPs a highly dynamic process. Precise regulation of this process is essential, as failure to assemble or disassemble an appropriate mRNP complex leads to disruption of downstream events such as mRNA export, translation, and decay, which have direct impacts on gene expression (Hieronymus and Silver 2004;Keene 2010;Wilusz and Wilusz 2010). Despite its fundamental importance, our knowledge of mRNP remodeling is limited and mostly emerged from two types of studies involving either RNA helicases or individual protein factors that associate with a defined mRNP in a spatially and/or temporally regu- RNA helicases of the DEAD-box family are an important group of RNA-remodeling proteins. These proteins are ATPases that use ATP to unwind RNA duplexes and remodel RNA-protein complexes (Linder and Jankowsky 2011; Pyle 2011). Distinct RNA helicases play important roles in every step of RNA metabolism (Linder and Jankowsky 2011). However, given the central role of RNA molecules in every aspect of cellular metabolism, it is expected that other types of ATPases function as additional motor proteins in RNA metabolism. In this study, we describe a previously uncharacterized role of a member of the AAA (ATPases associated with diverse cellular activities) family of proteins, vasolin-containing protein (VCP)/p97 (also called cdc48 in yeast), in mRNA stability control.p97 is considered a protein-remodeling machine (Meyer et al. 2012). It has two ATPase domains, D1 and D2, and uses the energy of ATP hydrolysis to r...

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Ubiquitin-mediated proteolysis of HuR by heat shock

Cited by 153 publications

References 56 publications

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

RNA regulons and the RNA-protein interaction network

The p97–UBXD8 complex destabilizes mRNA by promoting release of ubiquitinated HuR from mRNP

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