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Functional interactions between mRNA turnover and surveillance and the ubiquitin proteasome system

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Abstract The proteasome is a critical regulator of protein levels within the cell and is essential for maintaining homeostasis. A functional proteasome is required for effective mRNA surveillance and turnover. During transcription, the proteasome localizes to sites of DNA breaks, degrading RNA polymerase II and terminating transcription. For fully transcribed and processed messages, cytoplasmic surveillance is initiated with the pioneer round of translation. The proteasome is recruited to messages bearing premature termination codons, which trigger nonsense‐mediated decay (NMD), as well as messages lacking a termination codon, which trigger nonstop decay, to degrade the aberrant protein produced from these messages. A number of proteins involved in mRNA translation are regulated in part by proteasome‐mediated decay, including the initiation factors eIF4G, eIF4E, and eIF3a, and the poly(A)‐binding protein (PABP) interacting protein, Paip2. eIF4E‐BP (4E‐BP) is differentially regulated by the proteasome: truncated to generate a protein with higher eIF4B binding or completely degraded, depending on its phosphorylation status. Finally, a functional proteasome is required for AU‐rich‐element (ARE)‐mediated decay but the specific role the proteasome plays is unclear. There is data indicating the proteasome can bind to AREs, act as an endonuclease, and degrade ARE‐binding proteins. How these events interact with the 5′‐to‐3′ and 3′‐to‐5′ decay pathways is unclear at this time; however, data is provided indicating that proteasomes colocalize with Xrn1 and the exosome RNases Rrp44 and Rrp6 in untreated HeLa cells. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Mechanisms

Protein ubiquitylation pathway. (a) Primary amino acid sequence of ubiquitin. (b) Ribbon model of ubiquitin. The six lysines are shown in yellow. (c) Target proteins can be modified with single ubiquitins, multiple ubiquitins, and ubiquitin chains. Only ubiquitin chains linked through K48 target a protein for proteasomal degradation. (d) Protein ubiquitylation is a multistep process resulting in the covalent attachment of ubiquitin to a protein. Ubiquitin is attached to an E1 in an ATP‐dependent process and then the ubiquitin is transferred to an E2. E3s serve as specificity determinants with each E3 interacting with one or several protein ligands. For really interesting new gene and Ub‐fold E3s, ubiquitin is transferred directly from the E2 to the target protein; for homologous to E6‐associated protein C‐terminus E3s, the ubiquitin is first transferred to the E3 and then the target protein.

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mRNA surveillance and decay pathways. (a) AU‐rich‐element (ARE)‐mediated decay. TTP is the best‐studied decay mediating ARE‐binding protein.50 TTP has been shown to interact with components of both the PARN and CCR4 deadenylation complexes, the decapping enzyme Dcp1 and components of the 5′‐to‐3′ Xrn1‐mediated decay pathway, the 3′‐to‐5′ exosome decay pathway, and the RNA induced silencing complex members Argonaut 2 and 4. TTP protein is rapidly turned over by the proteasome and, in a poorly understood mechanism, TTP turnover is linked with mRNA decay. (b) Nonsense‐mediated decay (NMD). The presence of a premature termination codon in a message triggers NMD. A poor interaction between poly(A)‐binding protein and Upf1 when the ribosome reaches the stop codon results in the phosphorylation of Upf1 by SMG‐1 and the release of eRF1 and eRF3. Upf1 recruits the proteasome to destroy the truncated protein product as well as both the exosome and Xrn1 decay complexes to degrade the premature termination codon containing message. (c) Nonstop decay (NSD). The absence of a stop codon triggers NSD. The presence of a poly‐lysine chain at the carboxyl end of the protein, resulting from translation of the poly(A) tail, results in translational arrest followed by Not4‐mediated ubiquitylation of the protein. The protein is then cotranslationally degraded by the proteasome and the message subsequently degraded by both the 3′‐to‐5′ and 5′‐to‐3′ decay pathways. (d) No‐Go decay. Ribosomal stalling can result in the endonucleolytic cleavage of the mRNA, release of the ribosome, and decay of the message by the exosome and Xrn1.

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Proteasome control of translation. The proteins outlined in red are subject to proteasome‐mediated degradation or truncation. The elongation initiation factors 4E, 4G and 3 are all subject to proteasome‐mediated degradation. The eIF4E‐binding protein (4E‐BP) is subject to two different proteasome‐mediated events. In its hypophosphorylated state, 4E‐BP is cleaved (Tr‐4E‐BP) to generate a truncated version of the protein which binds eIF4E in preference to full‐length 4E‐BP. In its hyperphosphorylated state, 4E‐BP is completely degraded by the proteasome. PAIP2 levels are regulated by proteasome‐mediated degradation. PAIP2 competes with PAIP1 for binding to poly(A)‐binding protein (PABP). PAIP2 binding to PABP destabilizes the interaction of PABP with the polyadenylated tail of the message, decreasing translation efficiency and enhancing message decay.

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The 26S proteasome. (a) Schematic of the protein members of the 26S proteasome. The α‐ring proteins highlighted in red have RNase activity. (b) Schematic cross section of the 26S proteasome with specific functions indicated.

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RNase localization. HeLa cells were grown on cover slips, fixed, and stained according to the protocol in Kedersha and Anderson (2007) with the indicated antibodies. Nuclei were counter stained with Hoechst dye. For each panel, the white box in the left hand image represents the enlarged area on the right. (a) Xrn1, Psma5, and Rrp44 colocalize with each other in a subset of granules present in untreated HeLa cells. (b) Xrn1, Psma5, and Rrp6 colocalize with each other in a subset of granules present in untreated HeLa cells. An Xrn1 and Psma5 granule (yellow) is also present in the lower right of the enlarged area. Antibodies: Goat anti‐Xrn1 (1:500) (Santa Cruz sc‐50209); rabbit anti‐Psma5 (1:500) (Abcam ab11437); mouse anti‐Rrp44 (1:200) (Abcam ab68570); mouse anti‐Rrp6 (1:200) (Abnova H00005394‐M08). Donkey Fab fragment secondary antibodies from Jackson Research: Cy2‐goat (1:200), Cy3‐rabbit (1:2000), and Cy‐5‐mouse (1:200). Images were obtained using a Nikon Eclipse 80i with a 60× oil objective and analyzed using NIS‐Elements BR 3.0 software.

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Life cycle of mRNA. Birth of an mRNA begins with RNA‐polymerase II‐mediated transcription from a chromosomal gene sequence. Packaging of the message into an mRNP begins almost immediately with the initiation of transcription, with addition of the m7GpppG cap. Intron splicing from the pre‐mRNA can also begin before transcription is complete and results in the deposition of the exon‐junction complex (EJC). Upon transcriptional termination, the 3′ end is processed resulting in the addition of the poly(A) tail. Nuclear export of the mature message is a regulated process which in metazoans involves the EJC. Once in the cytoplasm, the message undergoes a pioneer round of translation which removes many of the proteins bound to the mRNA in the nucleus and these proteins shuttle back into the nucleus. In mammalian cells, the message is subject to several cytoplasmic surveillance mechanisms (Figure 5) during the pioneer round of translation. If the surveillance decay mechanisms are not activated, then the message is either translated into protein, stored for later translation, or degraded. Message degradation utilizes both the 5′‐to‐3′ Xrn1 and 3′‐to‐5′ exosome‐mediated decay pathways.

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability
Translation > Translation Mechanisms

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