Distinct mRNAs That Encode La Autoantigen Are Differentially Expressed and Contain Internal Ribosome Entry Sites

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Abstract
Analysis by reverse transcription-polymerase chain reaction has suggested the existence of at least two La autoantigen-encoding mRNAs that contain different 5′ noncoding regions (NCRs) linked to the same La coding region (Troster, H., Metzger, T. E., Semsei, I., Schwemmle, M., Winterpacht, A., Zabel, B., and Bachmann, M. (1994) J. Exp. Med.180, 2059–2067). La-encoding transcripts La1 and La1′ contain 115- and 483-nucleotide 5′ NCRs, respectively. To determine whether the various La transcripts are functional mRNAs, the expression and polysomal association of natural La1 and La1′ RNAs were examined. Although La1 transcripts were ubiquitously expressed in human tissues, La1′ transcripts were predominantly expressed in peripheral blood leukocytes, especially in B, T, and natural killer cells. Both La1 and La1′ transcripts associated with polysomes in natural killer cells, suggesting that these transcripts were functional mRNAs. Upon activation of B cells with the mitogens phorbol 12-myristate 13-acetate and ionomycin, the amount of La1′ mRNA, but not La1, declined. In contrast, after chemical activation of T cells, the amount of La 1 mRNA, but not La1′, declined. The mechanism by which the La1 and La1′ 5′ NCRs initiate translation initiation was tested in cultured human HeLa cells and in two different in vitro translation systems. It was found that both 5′ NCRs can mediate translation initiation by internal initiation. These findings indicate that the constitutive expression of La1 mRNA and the tissue-specific expression of La1′ mRNA can both allow La protein synthesis under conditions when cap-dependent translation is compromised, such as inflammation, apoptosis, or certain viral infections.