A post-transcriptional regulon controlled by TtpA, the single tristetraprolin family member expressed in Dictyostelium discoideum

• Published in: Nucleic acids research Vol. 49; no. 20; pp. 11920 - 11937
• Main Authors: Bai, Wenli, Wells, Melissa L, Lai, Wi S, Hicks, Stephanie N, Burkholder, Adam B, Perera, Lalith, Kimmel, Alan R, Blackshear, Perry J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 18.11.2021
• Subjects: 3' Untranslated Regions; Dictyostelium - genetics; Dictyostelium - metabolism; Mutation; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Regulon; RNA and RNA-protein complexes; RNA Stability; RNA, Messenger - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tristetraprolin - genetics; Tristetraprolin - metabolism
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkab983

Abstract Post-transcriptional processes mediated by mRNA binding proteins represent important control points in gene expression. In eukaryotes, mRNAs containing specific AU-rich motifs are regulated by binding of tristetraprolin (TTP) family tandem zinc finger proteins, which promote mRNA deadenylation and decay, partly through interaction of a conserved C-terminal CNOT1 binding (CNB) domain with CCR4–NOT protein complexes. The social ameba Dictyostelium discoideum shared a common ancestor with humans more than a billion years ago, and expresses only one TTP family protein, TtpA, in contrast to three members expressed in humans. Evaluation of ttpA null-mutants identified six transcripts that were consistently upregulated compared to WT during growth and early development. The 3′-untranslated regions (3′-UTRs) of all six ‘TtpA-target’ mRNAs contained multiple TTP binding motifs (UUAUUUAUU), and one 3′-UTR conferred TtpA post-transcriptional stability regulation to a heterologous mRNA that was abrogated by mutations in the core TTP-binding motifs. All six target transcripts were upregulated to similar extents in a C-terminal truncation mutant, in contrast to less severe effects of analogous mutants in mice. All six target transcripts encoded probable membrane proteins. In Dictyostelium, TtpA may control an ‘RNA regulon’, where a single RNA binding protein, TtpA, post-transcriptionally co-regulates expression of several functionally related proteins.