生物谷報(bào)道：轉(zhuǎn)錄水平的基因表達(dá)沉默已經(jīng)了解比較透徹,，但是對(duì)于翻譯水平的沉默則是剛剛起步,，也僅在tRNA合成酶表達(dá)時(shí)出現(xiàn),，但它仍十分有趣，且具有極深的研究?jī)r(jià)值,，它提出一個(gè)科學(xué)問(wèn)題----翻譯水平如何實(shí)現(xiàn)沉默,？

Aminoacyl tRNA synthetases are ancient proteins that appeared before the split of the tree of life into its three great kingdoms—archae, eukarya, and bacteria. The 20 enzymes—one for each amino acid—catalyze aminoacylation of tRNAs and thereby establish the rules of the genetic code by associating each amino acid with a nucleotide triplet (the anticodon of the tRNA). The transition from the RNA world to the theater of proteins was thus made possible by the development of specific aminoacylation reactions. While the central connection between synthetases and the code has long been recognized, the modern enzymes have surprised us with novel functions beyond aminoacylation. They are key regulators and active components in a wide range of cellular functions from RNA splicing and transcription to apoptosis and angiogenesis. The latest is reported in this issue of Cell by Sampath et al. (2004), who show that gene-specific translational silencing is executed by a long-mysterious, bipartite tRNA synthetase.

The two-part enzyme is a fusion of glutamyl- and prolyl-tRNA synthetase (GluProRS) that is found only in higher eukaryotes (Fett and Knippers, 1991). A linker of three repeats of roughly 50 amino acids, which each seem to adopt a helix-turn-helix structure (Jeong et al., 2000), joins the two synthetases, although the rationale for the fusion is not known. GluProRS is also a component of a multisynthetase complex that has been well studied and characterized by various laboratories (Cerini et al. 1991; Negrutskii et al. 1994 and Norcum and Dignam 1999). Sampath et al. (2004) show that GluProRS is an essential component of a four-protein complex that silences translation of ceruloplasmin (Cp), a protein linked to the inflammatory response (Bielli and Calabrese, 2002). -interferon mobilizes GluProRS, releasing it from the synthetase complex by promoting phosphorylation of one or more serines. Once mobilized, it inhibits translation of Cp by binding together with three other proteins to the 3′-untranslated region of the Cp mRNA to form a -interferon-activated inhibitor of translation (GAIT) complex. De novo synthesis of GluProRS is not required for GAIT complex formation. Instead, all of the GluProRS that appears in the complex seems to be accounted for by its depletion from the multisynthetase complex.

Previous work showed that binding to Cp mRNA is through a specific RNA hairpin known as a GAIT element (Sampath et al., 2003). Here it is shown that, although GluProRS can bind directly to the GAIT RNA element, translation inhibition involves the full four-protein GAIT complex. In their model, the silencing process starts with formation of a pre-GAIT complex between GluProRS and NS1-associated protein-1 (NSAP1), a nuclear ribonucleoprotein. Two other proteins—phosphorylated ribosomal protein L13a (L13ap) and GAPDH—join to complete the complex that shuts down translation. The elements needed for protein-protein contacts in this complex are not defined. None of the proteins other than GluProRS binds directly to the GAIT RNA element, so it seems likely that the bipartite synthetase holds the proteins to the RNA.

Although the motif in GluProRS that contacts the GAIT element is not yet defined, the repeating linker has RNA binding activity (Jeong et al., 2000) and remains a plausible candidate. In addition, each of the fused synthetases has a tRNA binding site that, conceivably, could correspond to or overlap with the site needed for GAIT element binding. But even if the linker is there to interact with the GAIT element, it is unclear as to why it is presented in the context of two joined synthetases and why the two synthetases were joined together in the first place. Because the fusion is seen only in higher eukaryotes, where complex regulatory mechanisms not seen in lower organisms are common, the Sampath et al. (2004) work invites speculation that the connection between activity for translational silencing and fusion of GluRS and ProRS is something more than random coincidence.

As a multifunctional oxidase linked to the inflammatory response, Cp is not the only example of a link between inflammation and a noncanonical role for a tRNA synthetase. Other cases include the stimulation of inflammatory cytokines by specific forms of mammalian TyrRS and the leukocyte chemotactic activity of HisRS (Wakasugi and Schimmel 1999 and Howard et al. 2002). Plausibly, GluProRS regulates other transcripts that bear GAIT elements in their 3′UTRs (more than 30 in human cells have been cataloged [Sampath et al., 2003]). Several of these are associated with transcripts encoding proteins involved in inflammatory pathways. Thus, translational silencing of Cp expression by GluProRS may be coordinated with silencing of other inflammation-related transcripts. In contrast to GluProRS, the specific forms of TyrRS and HisRS that regulate the inflammatory response act through extracellular receptors. Thus, GluProRS is the first example of a tRNA synthetase acting on inflammation through an intracellular pathway. With the Sampath et al. (2004) work, we now see that tRNA synthetases in mammalian cells have more diverse and comprehensive connections to the inflammatory system than was previously appreciated. The diverse functions of these essential enzymes never cease to amaze!

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