Roles of polyamines in translation

Abstract

Polyamines are organic polycations that bind to a variety of cellular molecules, including nucleic acids. Within cells, polyamines contribute to both the efficiency and fidelity of protein synthesis. In addition to directly acting on the translation apparatus to stimulate protein synthesis, the polyamine spermidine serves as a precursor for the essential post-translational modification of the eukaryotic translation factor 5A (eIF5A), which is required for synthesis of proteins containing problematic amino acid sequence motifs, including polyproline tracts, and for termination of translation. The impact of polyamines on translation is highlighted by autoregulation of the translation of mRNAs encoding key metabolic and regulatory proteins in the polyamine biosynthesis pathway, including S-adenosylmethionine decarboxylase (AdoMetDC), antizyme (OAZ), and antizyme inhibitor 1 (AZIN1). Here, we highlight the roles of polyamines in general translation and also in the translational regulation of polyamine biosynthesis.

Keywords: AdoMetDC; antizyme; antizyme inhibitor; autoregulation; eukaryotic initiation factor 5A (eIF5A); ornithine decarboxylase; polyamine; spermidine; translation; translation regulation.

Figure 1.

Schematic representation of polyamine control of OAZ, AZIN, and AdoMetDC mRNA translation. A, OAZ is encoded by two partially overlapping ORFs linked through ribosomal +1 frameshifting. Under lower polyamine conditions (left), ribosomes terminate at the stop codon of ORF1; under higher polyamine conditions (right), ribosomes frameshift at the ORF1 stop codon and synthesize full-length OAZ. B, AZIN and some ODC mRNAs contain a uCC element (in red, an inhibitory uORF with conserved peptide sequence and initiated at a near cognate start codon) upstream of the main ORF (green). In lower polyamine conditions, many scanning ribosomes bypass the uCC and translate the main ORF, and ribosomes that translate the uCC disengage from the mRNA after terminating. Under higher polyamine conditions, translating ribosomes pause during translation of the uCC and cause queuing of subsequent scanning ribosomes and enhanced initiation on the uCC. The increased translation of the uCC results in decreased translation of the main ORF. C, AdoMetDC mRNAs of vertebrates contain an inhibitory uORF (red) encoding a peptide with the sequence MAGDIS; the main ORF is in green. Under conditions of lower polyamines, many ribosomes bypass the uORF and translate the main ORF. The occasional ribosome that translates the uORF disengages from the mRNA after termination. Under conditions of higher polyamines, pausing of translating ribosomes at the uORF stop codon blocks additional ribosomes from loading on the mRNA and impairs main ORF translation.