The Yeast Ccr4-Not Complex Controls Ubiquitination of the Nascent-associated Polypeptide (NAC-EGD) Complex

Panasenko, Olesya O.; Landrieux, Emilie; Feuermann, Marc; Finka, Andrija; Paquet, Nicole; Collart, Martine A.

doi:10.1074/jbc.m604986200

Cited by 94 publications

(132 citation statements)

References 39 publications

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“…The CCR4/NOT complex appears to be a major mRNA deadenylase in yeast and Drosophila (Tucker et al 2001;Temme et al 2004) and has been implicated in miRNA-dependent mRNA degradation (Behm-Ansmant et al 2006). In addition, the CCR4/NOT complex may have roles in transcriptional regulation (Winkler et al 2006) and protein ubiquitination (Panasenko et al 2006). In C. elegans, let-711/ntl-1, ntl-2, and most other putative subunits of the CCR/ NOT complex are essential, as might be expected for genes that play widespread roles in mRNA metabolism (Gonczy et al 2000;Maeda et al 2001;Kamath et al 2003;Simmer et al 2003;Rual et al 2004;Molin and Puisieux 2005;Sonnichsen et al 2005;Debella et al 2006).…”

Section: Resultsmentioning

confidence: 99%

The Caenorhabditis elegans ekl (Enhancer of ksr-1 Lethality) Genes Include Putative Components of a Germline Small RNA Pathway

et al. 2008

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A canonical Ras-ERK signaling pathway specifies the fate of the excretory duct cell during Caenorhabditis elegans embryogenesis. The paralogs ksr-1 and ksr-2 encode scaffolding proteins that facilitate signaling through this pathway and that act redundantly to promote the excretory duct fate. In a genomewide RNAi screen for genes that, like ksr-2, are required in combination with ksr-1 for the excretory duct cell fate, we identified 16 ''ekl '' (enhancer of ksr-1 lethality) genes that are largely maternally required and that have molecular identities suggesting roles in transcriptional or post-transcriptional gene regulation. These include the Argonaute gene csr-1 and a specific subset of other genes implicated in endogenous small RNA processes, orthologs of multiple components of the NuA4/Tip60 histone acetyltransferase and CCR4/NOT deadenylase complexes, and conserved enzymes involved in ubiquitination and deubiquitination. The identification of four small RNA regulators (csr-1, drh-3, ego-1, and ekl-1) that share the Ekl phenotype suggests that these genes define a functional pathway required for the production and/or function of particular germline small RNA(s). These small RNAs and the other ekl genes likely control the expression of one or more regulators of Ras-ERK signaling that function at or near the level of kinase suppressor of Ras (KSR).

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Section: Resultsmentioning

confidence: 99%

The Caenorhabditis elegans ekl (Enhancer of ksr-1 Lethality) Genes Include Putative Components of a Germline Small RNA Pathway

et al. 2008

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“…41 In addition, the Saccharomyces cerevisiae NAC complex (EGD), which consists of Egd1p (bNAC) and Egd2p (aNAC), can be ubiquitinated in vitro through a UBA domain at the C terminus of the Egd2p. 42 In hypoxic cells, aNAC but not bNAC might be degraded through the ubiquitin-protease system (UBS). However, cells undergoing ER stress may exhibit general inhibition of the UBS due to the presence of aberrant ubiquitin.…”

Section: Discussionmentioning

confidence: 99%

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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Accumulation of unfolded proteins triggers endoplasmic reticulum (ER) stress and is considered a part of the cellular responses to hypoxia. The nascent polypeptide-associated complex (NAC) participates in the proper maturation of newly synthesized proteins. However, thus far, there have been no comprehensive studies on NAC involvement in hypoxic stress. Here, we show that hypoxia activates glycogen synthase kinase-3b (GSK-3b) and that the activated GSK-3b destabilizes aNAC with the subsequent apoptosis of the cell. Hypoxia of various cell types and the mouse ischemic brain was associated with rapid downregulation of aNAC and ER stress responses involving PERK, ATF4, c-taxilin, elF2a, Bip, and CHOP. Depletion of aNAC by RNA interference specifically activated ER stress responses and caused mitochondrial dysfunction, which resulted in apoptosis through caspase activation. Interestingly, we found that the hypoxic conditions activated GSK-3b, and that GSK-3b inhibition prevented aNAC protein downregulation in hypoxic cells and rescued the cells from apoptosis. In addition, aNAC overexpression increased the viability of hypoxic cells. Taken together, these results suggest that aNAC degradation triggers ER stress responses and initiates apoptotic processes in hypoxic cells, and that GSK-3b may participate upstream in this mechanism.

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“…However, yeast NAC homolog (termed as EGD complex) is not prerequisite for growth (Reimann et al, 1999), but is necessary for protein targeting to mitochondria (George et al, 1998;Fünfschilling and Rospert, 1999). In addition, in yeast both subunits including their NAC domains have been shown to be ubiquitinated in a lysine dependent manner (Panasenko et al, 2006(Panasenko et al, , 2009. Besides functioning in cytosol, NAC can tightly bind in nucleus with X-junction in DNA replication forks and homolog recombinant regions (Whitby and Dixon, 2001).…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of NAC domains of human nascent polypeptide-associated complex (NAC) and its αNAC subunit

et al. 2010

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Nascent polypeptide associated complex (NAC) and its two isolated subunits, αNAC and βNAC, play important roles in nascent peptide targeting. We determined a 1.9 Å resolution crystal structure of the interaction core of NAC heterodimer and a 2.4 Å resolution crystal structure of αNAC NAC domain homodimer. These structures provide detailed information of NAC heterodimerization and αNAC homodimerization. We found that the NAC domains of αNAC and βNAC share very similar folding despite of their relative low identity of amino acid sequences. Furthermore, different electric charge distributions of the two subunits at the NAC interface provide an explanation to the observation that the heterodimer of NAC complex is more stable than the single subunit homodimer. In addition, we successfully built a βNAC NAC domain homodimer model based on homologous modeling, suggesting that NAC domain dimerization is a general property of the NAC family. These 3D structures allow further studies on structurefunction relationship of NAC.

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The Yeast Ccr4-Not Complex Controls Ubiquitination of the Nascent-associated Polypeptide (NAC-EGD) Complex

Cited by 94 publications

References 39 publications

The Caenorhabditis elegans ekl (Enhancer of ksr-1 Lethality) Genes Include Putative Components of a Germline Small RNA Pathway

The Caenorhabditis elegans ekl (Enhancer of ksr-1 Lethality) Genes Include Putative Components of a Germline Small RNA Pathway

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Crystal structures of NAC domains of human nascent polypeptide-associated complex (NAC) and its αNAC subunit

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