Hmt1 is the major type I arginine methyltransferase in the yeastIn eukaryotic cells, pre-messenger RNAs (pre-mRNAs) must be fully processed and packaged into mature messenger ribonucleoparticles (mRNPs) before export to the cytoplasm as fully translatable mRNAs. Intranuclear RNA processing steps, such as 5Ј-capping, splicing, 3Ј-end cleavage, and polyadenylation, are accomplished through the association of numerous RNA-binding proteins (RBPs) such as serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) with the pre-mRNA (for review, see Dreyfuss et al. 2002;Lei and Silver 2002b;Reed and Hurt 2002). Many RBPs that participate in RNA processing and export contain a variety of posttranslational modifications such as phosphorylation and methylation. The dynamic interactions between RBPs and pre-mRNAs suggest that their binding to and dissociation from RNAs and other proteins may be regulated by these posttranslational modifications.One type of posttranslational modification commonly found in RNA-binding proteins is the methylation of arginine residues, usually in the context of arginine-and glycine-rich motifs (for review, see Gary and Clarke 1998). The enzymes that catalyze this process are called protein arginine methyltransferase, or PRMTs. hnRNPs are a major substrate of PRMT1 in yeast and mammalian cells. Methylated hnRNPs contain at least one N-terminal RRM-type (RNA recognition motif) RNA-binding motif in conjunction with RGG-rich (arginine-glycineglycine) repeats, the sites of arginine methylation, in the C-terminal domains (Liu and Dreyfuss 1995).Recent studies have shown that arginine methylation is important for modulating protein-protein interactions. For example, loss of arginine methylation on the STAT1 protein inhibits association with its inhibitor PIAS, resulting in decreased interferon responses mediated by STAT1 (Mowen et al. 2001). Methylation of the Src kinase substrate Sam68 has been shown to change its affinity for SH3-containing proteins, resulting in alteration of its function (Bedford et al. 2000). In addition, arginine methylation of the transcriptional elongation factor Spt5 regulates its interaction with RNA polymerase (Pol) II, thereby globally affecting transcription (Kwak et al. 2003). However, the precise role of methylation of the many RBPs remains unclear.
Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFjB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFjB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IjBa), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFjB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.
Nuclear export of mRNA is a central step in gene expression that shows extensive coupling to transcription and transcript processing. However, little is known about the fate of mRNA and its export under conditions that damage the DNA template and RNA itself. Here we report the discovery of four new factors required for mRNA export through a screen of all annotated nonessential Saccharomyces cerevisiae genes. Two of these factors, mRNA surveillance factor Rrp6 and DNA repair protein Lrp1, are nuclear exosome components that physically interact with one another. We find that Lrp1 mediates specific mRNA degradation upon DNA-damaging UV irradiation as well as general mRNA degradation. Lrp1 requires Rrp6 for genomic localization to genes encoding its mRNA targets, and Rrp6 genomic localization in turn correlates with transcription. Further, Rrp6 and Lrp1 are both required for repair of UV-induced DNA damage. These results demonstrate coupling of mRNA surveillance to mRNA export and suggest specificity of the RNA surveillance machinery for different transcript populations. Broadly, these findings link DNA and RNA surveillance to mRNA export.[Keywords: mRNA export; mRNA surveillance; DNA repair; nuclear exosome; Lrp1; Rrp6] Supplemental material is available at http://www.genesdev.org.
The three ribosomal proteins L7, S5, and S18 are included in the rare subset of prokaryotic proteins that are known to be N a -acetylated. The GCN5-related N-acetyltransferase (GNAT) protein RimI, responsible for the N a -acetylation of the ribosomal protein S18, was cloned from Salmonella typhimurium LT2 (RimI ST ), overexpressed, and purified to homogeneity. Steady-state kinetic parameters for RimI ST were determined for AcCoA and a peptide substrate consisting of the first six amino acids of the target protein S18. The crystal structure of RimI ST was determined in complex with CoA, AcCoA, and a CoA-S-acetyl-ARYFRR bisubstrate inhibitor. The structures are consistent with a direct nucleophilic addition-elimination mechanism with Glu103 and Tyr115 acting as the catalytic base and acid, respectively. The RimI ST -bisubstrate complex suggests that several residues change conformation upon interacting with the N terminus of S18, including Glu103, the proposed active site base, facilitating proton exchange and catalysis.Keywords: protein N a -acetylation; bisubstrate inhibition; GNAT structure; ribosomal protein Supplemental material: see www.proteinscience.orgThe bacterial ribosome is a complex biological machine composed of three ribosomal RNA (rRNA) 1 molecules and 55 proteins. However, it is poorly appreciated that the complexity of the ribosome is increased by posttranslational modifications to both the rRNA and ribosomal proteins. While these modifications, which include methylation and acetylation, have been known for decades, a complete understanding of how, when, and why these modifications are made and their contribution to the structure and function of the ribosome remain unknown. A better understanding of how ribosomal modifications are made, at what stage in ribosome biosynthesis they are made, and their influence on the structure or function of the ribosome would be useful for a complete understanding of ribosome assembly and function.Acetylation of the alpha amino group of protein N-terminal amino acids is very common in eukaryotes. In some cells, estimates have shown more than half of all proteins are N a -acetylated (Driessen et al. 1985;Bradshaw et al. 1998). However, the number of N aacetylated proteins in prokaryotes is limited to seven known examples (Table 1). It is not known why ribosomal proteins are overrepresented in this list, nor is the function of any of the acetylations known. Furthermore, except for RimI, RimJ, and RimL, which N a -acetylate the ribosomal proteins S18, S5, and L12, respectively, the , RimI from Salmonella typhimurium LT2; bisubstrate inhibitor, CoA-S-acetyl-S18 1-6 ; RMSD, root-mean-squared deviation.Article and publication are at
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