Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor

Article (PDF Available)inThe FASEB Journal 24(12):4917-28 · December 2010with26 Reads
DOI: 10.1096/fj.10-162636 · Source: PubMed
Growing evidence indicates a critical role of ubiquitin-proteosome system in apoptosis regulation. A cardioprotective effect of ubiquitin (Ub) ligase of the C terminus of Hsc70-interacting protein (CHIP) on myocytes has been reported. In the current study, we found that the cardioprotective effect of insulin growth factor-1 (IGF-1) was mediated by ERK5-CHIP signal module via inducible cAMP early repressor (ICER) destabilization. In vitro runoff assay and Ub assay showed ICER as a substrate of CHIP Ub ligase. Both disruption of ERK5-CHIP binding with inhibitory helical linker domain fragment (aa 101-200) of CHIP and the depletion of ERK5 by siRNA inhibited CHIP Ub ligase activity, which suggests an obligatory role of ERK5 on CHIP activation. Depletion of CHIP, using siRNA, inhibited IGF-1-mediated reduction of isoproterenol-mediated ICER induction and apoptosis. In diabetic mice subjected to myocardial infarction, the CHIP Ub ligase activity was decreased, with an increase in ICER expression. These changes were attenuated significantly in a cardiac-specific constitutively active form of MEK5α transgenic mice (CA-MEK5α-Tg) previously shown to have greater functional recovery. Furthermore, pressure overload-mediated ICER induction was enhanced in heterozygous CHIP(+/-) mice. We identified ICER as a novel CHIP substrate and that the ERK5-CHIP complex plays an obligatory role in inhibition of ICER expression, cardiomyocyte apoptosis, and cardiac dysfunction.


    • "A different therapeutic strategy was proposed to enhance the efficacy of anticancer drugs, through CHIP, by modulating CYP3A4 functioning (Peer et al., 2011). CHIP also has a pivotal role in cardiac disorders, where it provides cardioprotection by degrading inducible cAMP early repressor in complex with extracellular stress-regulated kinase 5 (Woo et al., 2010). All the above described roles of CHIP, in various disorders elucidate its significance for future research to develop advanced strategies to control these pathological disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Cells regularly synthesize new proteins to replace old and abnormal proteins for normal cellular functions. Two significant protein quality control pathways inside the cellular milieu are ubiquitin proteasome system (UPS) and autophagy. Autophagy is known for bulk clearance of cytoplasmic aggregated proteins, whereas the specificity of protein degradation by UPS comes from E3 ubiquitin ligases. Few E3 ubiquitin ligases, like C-terminus of Hsc70-interacting protein (CHIP) not only take part in protein quality control pathways, but also plays a key regulatory role in other cellular processes like signaling, development, DNA damage repair, immunity and aging. CHIP targets misfolded proteins for their degradation through proteasome, as well as autophagy; simultaneously, with the help of chaperones, it also regulates folding attempts for misfolded proteins. The broad range of CHIP substrates and their associations with multiple pathologies make it a key molecule to work upon and focus for future therapeutic interventions. E3 ubiquitin ligase CHIP interacts and degrades many protein inclusions formed in neurodegenerative diseases. The presence of CHIP at various nodes of cellular protein-protein interaction network presents this molecule as a potential candidate for further research. In this review, we have explored a wide range of functionality of CHIP inside cells by a detailed presentation of its co-chaperone, E3 and E4 enzyme like functions, with central focus on its protein quality control roles in neurodegenerative diseases. We have also raised many unexplored but expected fundamental questions regarding CHIP functions, which generate hopes for its future applications in research, as well as drug discovery.
    Full-text · Article · Oct 2016
    • "ERK5 is twice the size of the classical MAPKs (816 aa for human ERK5), containing an Nterminal kinase domain (aa 78–406) and a unique C-terminal tail (aa 410–816) with no homology to any other protein, which has an autoinhibitory function (Buschbeck and Ullrich, 2005). This C-terminal tail contains a myocyte enhancer factor 2 MEF2-interacting region (aa 440–501, Kasler et al., 2000), a bipartite nuclear localization signal NLS (aa 505–539), and a transcriptional activation domain (TAD, aa 664–789, Kasler et al., 2000), which associates with and activates several transcription factors (Morimoto et al., 2007; Woo et al., 2010). Activation of ERK5 requires dual phosphorylation of a Threonine and Tyrosine residues within a TEY motif in the activation loop of the kinase domain (Mody et al., 2003). "
    [Show abstract] [Hide abstract] ABSTRACT: ERK5, the last MAP kinase family member discovered, is activated by the upstream kinase MEK5 in response to growth factors and stress stimulation. MEK5-ERK5 pathway has been associated to different cellular processes, playing a crucial role in cell proliferation in normal and cancer cells by mechanisms that are both dependent and independent of its kinase activity. Thus, nuclear ERK5 activates transcription factors by either direct phosphorylation or acting as co-activator thanks to a unique transcriptional activation TAD domain located at its C-terminal tail. Consequently, ERK5 has been proposed as an interesting target to tackle different cancers, and either inhibitors of ERK5 activity or silencing the protein have shown antiproliferative activity in cancer cells and to block tumor growth in animal models. Here, we review the different mechanisms involved in ERK5 nuclear translocation and their consequences. Inactive ERK5 resides in the cytosol, forming a complex with Hsp90-Cdc37 superchaperone. In a canonical mechanism, MEK5-dependent activation results in ERK5 C-terminal autophosphorylation, Hsp90 dissociation, and nuclear translocation. This mechanism integrates signals such as growth factors and stresses that activate the MEK5-ERK5 pathway. Importantly, two other mechanisms, MEK5-independent, have been recently described. These mechanisms allow nuclear shuttling of kinase-inactive forms of ERK5. Although lacking kinase activity, these forms activate transcription by interacting with transcription factors through the TAD domain. Both mechanisms also require Hsp90 dissociation previous to nuclear translocation. One mechanism involves phosphorylation of the C-terminal tail of ERK5 by kinases that are activated during mitosis, such as Cyclin-dependent kinase-1. The second mechanism involves overexpression of chaperone Cdc37, an oncogene that is overexpressed in cancers such as prostate adenocarcinoma, where it collaborates with ERK5 to promote cell proliferation. Although some ERK5 kinase inhibitors have shown antiproliferative activity it is likely that those tumors expressing kinase-inactive nuclear ERK5 will not respond to these inhibitors.
    Full-text · Article · Sep 2016
    • "CHIP decreased p53 level via ubiquitination and proteasomal degradation. Furthermore, Woo et al., [90] found that the cardioprotective function of CHIP-ERK5 (extracellular signal-regulated kinase 5) interaction through destabilization of inducible cAMP early repressor (ICER). In contrast, dissociation of the complex via phosphorylation at S496 of ERK5 results to reversal of cardioprotective phenotype [91]. "
    [Show abstract] [Hide abstract] ABSTRACT: Carboxyl terminus of Hsc70-interacting protein (CHIP) is known as a chaperone-associated E3 for a variety of protein substrates. It acts as a link between molecular chaperones and ubiquitin-proteasome system. Involved in the process of protein clearance, CHIP plays a critical role in maintaining protein homeostasis in diverse conditions. Here, we provide a comprehensive review of our current understanding of CHIP and summarize recent advances in CHIP biology, with a focus on CHIP in the setting of malignancies.
    Full-text · Article · Mar 2016
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