The La protein is a target of autoantibodies in patients suffering from Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Ubiquitous in eukaryotes, La functions as a RNA-binding protein that promotes the maturation of tRNA precursors and other nascent transcripts synthesized by RNA polymerase III as well as other noncoding RNAs. La also associates with a class of mRNAs that encode ribosome subunits and precursors to snoRNAs involved in ribosome biogenesis. Thus, it was surprising that La is dispensable in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms from which it has been characterized most extensively. To determine whether La is essential in mammals and if so, at which developmental stage it is required, mice were created with a disrupted La gene, and the offspring from La ؉/؊ intercrosses were analyzed. La ؊/؊ offspring were detected at the expected frequency among blastocysts prior to implantation, whereas no nullizygotes were detected after implantation, indicating that La is required early in development. Blastocysts derived from La La antigen, also known as Sjögren's syndrome antigen B (SS-B), is a target of autoantibodies in patients suffering from systemic lupus erythematosus, neonatal lupus, and related disorders and exists in cells complexed with various RNAs (20). Homologs of La are present in all of the eukaryote genomes examined, and La proteins have been characterized in ciliates, yeasts, flies, frogs, and mammals (7,22,33). While La has been implicated in many RNA-related pathways, its most established role is protecting the UUU-OH 3Ј ends of precursor tRNAs and other small RNAs from digestion (21,23,29,33).Vertebrate La proteins can modulate the translation of mRNAs that contain internal ribosome entry sites, as well as mRNAs that contain 5Ј-terminal oligopyrimidine motifs that encode ribosome subunits and translation factors (8, 28; reviewed in reference 33). The association of human Mdm2 mRNA with La promotes MDM2 translation with consequent decrease in p53 protein level and leukemia progression (31). La is also found associated with mRNAs in Saccharomyces cerevisiae, including mRNAs that encode ribosome subunits (14). Deletion of La from yeasts leads to alterations in the maturation pathways of pre-tRNAs (2,5,6,16,17,26,35) and pre-snoRNAs involved in rRNA biogenesis (14, 21). Thus, it was surprising that La is nonessential in yeasts, except when tRNAs or RNA-associated factors acquire debilitating mutations (21, 29, 33) and upon a conditional induction of the unfolded protein response (14).The conserved N-terminal domain of La is comprised of a La motif and RNA recognition motif (RRM) that cooperate for high-affinity 3Ј UUU-OH binding (1, 9, 18). However, while these motifs constitute the La proteins of yeasts, metazoan La proteins also contain another, atypical RRM in their C termini (18).In the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms in which La has been characterized most extensively, La is dispens...
We previously identified a gene, termed Mblk-1, that encodes a putative transcription factor with two DNA-binding motifs expressed preferentially in the mushroom body of the honeybee brain, and its preferred binding sequence, termed Mblk-1-binding element (MBE) (Takeuchi, H., Kage, E., Sawata, M., Kamikouchi, A., Ohashi, K., Ohara, M., Fujiyuki, T., Kunieda, T., Sekimizu, K., Natori, S., and Kubo, T. The honeybee Apis mellifera L. is a social insect, and colony members perform various exquisite communications to maintain colony activities. Worker bees inform the other foragers of the direction and distance of a food source using dance language (1, 2), which might require complex processing of sensory information in their brains. Little is known, however, regarding the molecular basis of their highly advanced behavior.Mushroom bodies (MBs) 1 are believed to be involved in sensory integration, learning, and memory in insects (3, 4). The honeybee MBs are well developed when compared with those of other insects. In the honeybee, the ratio of volume of MBs to that of whole brain is ϳ12%, whereas that of Drosophila is ϳ2% (5). Moreover, each MB of the honeybee has two calyces composed of two morphologically distinct types of interneurons, the large-and small-type Kenyon cells (5-7). On the other hand, in Drosophila, there is only one calyx, and the Kenyon cells are morphologically indistinct (8). These observations suggest that MB function is closely associated with the advanced honeybee behaviors.To identify molecules involved in the highly advanced behaviors of the honeybees, we previously used the differential display method to identify a gene, termed Mblk-1, that is expressed preferentially in the large-type Kenyon cells of the honeybee brain (9). Mblk-1 encodes a novel protein consisting of 1598 amino acid residues with significant similarity to a nuclear factor encoded by the Drosophila melanogaster CG18389/E93 gene. The CG18389/E93 gene was identified previously as an ecdysone-inducible gene in the prepupal salivary gland (10) and was reported to encode a nuclear protein that is required for ecdysone-triggered programmed cell death during metamorphosis (11). The expression of CG18389/E93 in the adult and the biochemical characteristics of the protein, however, have not been examined.Two putative DNA-binding motifs, termed RHF (region conserved between honeybee and fruit fly) 1 and RHF2, a nuclear localization signal, and Gln run were conserved between Mblk-1 and Drosophila E93 protein (9). RHF2 has significant sequence homology with proteins encoded by genes from nematoda (a polypeptide predicted by an open reading frame of the Caenorhabditis elegans cosmid T01C1), human (three polypeptides predicted by open reading frames of the chromosome 4 clone RP11-173B23 map 4, chromosome 11 clone RP11-162M10 map 11, and chromosome 10 clone RP11-175019, respectively), mouse (12), and sea urchin (a polypeptide predicted by an open reading frame of the Strongylocentrotus purpuratus EST253 coelomocyte cDNA 5Ј-end), suggestin...
The La protein interacts with a variety of small RNAs as well as certain growth-associated mRNAs such as Mdm2 mRNA. Human La (hLa) phosphoprotein is so highly conserved that it can replace the tRNA processing function of the fission yeast La protein in vivo. We used this system, which is based on tRNA-mediated suppression (TMS) of ade6-704 in S. pombe, to compare the activities of mouse and human La proteins. Prior studies indicate that hLa is activated by phosphorylation of serine-366 by protein kinase CK2, neutralizing a negative effect of a short basic motif (SBM). First, we report the sequence mapping of the UGA stop codon that requires suppressor tRNA for TMS, to an unexpected site in S. pombe ade6-704. Next, we show that, unlike hLa, native mLa is unexpectedly inactive for TMS, although its intrinsic activity is revealed by deletion of its SBM. We then show that mLa is not phosphorylated by CK2, accounting for the mechanistic difference between mLa and hLa. We found a PKA/PKG target sequence in mLa (S199) that is not present in hLa, and show that PKA/PKG efficiently phosphorylates mLa S199 in vitro. A noteworthy conclusion that comes from this work is that this fission yeast system can be used to gain insight into differences in control mechanisms used by La proteins of different mammalian species. Finally, RNA binding assays indicate that while mutation of mLa S199 has little effect on pre-tRNA binding, it substantially decreases binding to a probe derived from Mdm2 mRNA. In closing, we note that species-specific signaling through La may be relevant to the La-dependent Mdm2 pathways of p53 metabolism and cancer progression in mice and humans.
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