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J. Biol. Chem., Vol. 277, Issue 38, 35738-35745, September 20, 2002

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Lactate Dehydrogenase Is an AU-rich Element-binding Protein That Directly Interacts with AUF1^*

Patricia A. Pioli, B. JoNell Hamilton, John E. Connolly, Gary Brewer^§, and William F. C. Rigby^¶

From the  Departments of Medicine and Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756 and ^§ Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Post-transcriptional pathways provide a major means of regulating eukaryotic gene expression. Reiterations of the AU-rich element (ARE) within the 3'-untranslated region of many cytokine and proto-oncogene mRNAs serve as signals for rapid degradation and translational repression. The identification of this cis-acting stability determinant has fueled the search for ARE-binding proteins (AUBP) that function as trans-acting factors that transduce this function. Previous work identified heterogeneous nuclear ribonucleoprotein (hnRNP) A1 as a major AUBP capable of binding the ARE of granulocyte-macrophage colony stimulating factor (GM-CSF) RNA in the context of a full-length mRNA. We report here that functional studies failed to indicate a role for hnRNP A1 in ARE-dependent mRNA turnover. In an effort to identify other functionally relevant AUBP, the major GM-CSF ARE-specific binding protein in cells lacking hnRNP A1 was purified from CB3 mouse erythroleukemia cells. Microsequencing identified this protein as the glycolytic enzyme lactate dehydrogenase (LDH) M. RNA binding by LDH was shown to occur in the NAD⁺-binding region (Rossmann fold). Polysome gradient analysis demonstrates that LDH is found in the translationally active fraction. Polysomal localization of LDH was dependent on RNA binding. Moreover, polysomal LDH exists in a complex with AUF1 and hsp-70, which has been implicated previously in the regulation of mRNA turnover. The interaction between LDH and AUF1 is direct as it can be demonstrated in vitro with purified proteins. Collectively these data implicate a role for LDH in the post-transcriptional regulation of gene expression.

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