Abstract
Degradation of ornithine decarboxylase, the rate-limiting enzyme of polyamine biosynthesis, is promoted by the protein antizyme. Expression of antizyme is positively regulated by rising polyamine concentrations that induce a +1 translational frameshift required for production of the full-length protein. Antizyme itself is negatively regulated by the antizyme inhibitor. In our study, the regulation of Caenorhabditis elegans antizyme was investigated, and the antizyme inhibitor was identified. By applying a novel GFP-based method to monitor antizyme frameshifting in vivo, we show that the induction of translational frameshifting also occurs under stressful conditions. Interestingly, during starvation, the initiation of frameshifting was independent of polyamine concentrations. Because frameshifting was also prevalent in a polyamine auxotroph double mutant, a polyamine-independent regulation of antizyme frameshifting is suggested. Polyamine-independent induction of antizyme expression was found to be negatively regulated by the peptide transporter PEPT-1, as well as the target of rapamycin, but not by the daf-2 insulin signaling pathway. Stress-dependent expression of C. elegans antizyme occurred morely slowly than expression in response to increased polyamine levels, pointing to a more general reaction to unfavorable conditions and a diversion away from proliferation and reproduction toward conservation of energy. Interestingly, antizyme expression was found to drastically increase in aging individuals in a postreproductive manner. Although knockdown of antizyme did not affect the lifespan of C. elegans, knockdown of the antizyme inhibitor led to a significant reduction in lifespan. This is most likely caused by an increase in antizyme-mediated degradation of ornithine decarboxylase-1 and a resulting reduction in cellular polyamine levels.
Highlights
Ornithine decarboxylase degradation by the proteasome is promoted by antizyme
Physical Interaction between C. elegans Antizyme and the Putative Antizyme Inhibitor—Our first goal was to establish whether the regulatory circuit between ornithine decarboxylase (ODC), antizyme, and antizyme inhibitor for C. elegans complies with the well known
Because protein sequences of ODC and antizyme inhibitor (AZI) are usually very similar, we identified the gene F53F10.2, which is annotated as a C. elegans ODC-1 paralogue, to be the most likely candidate for C. elegans AZI
Summary
Ornithine decarboxylase degradation by the proteasome is promoted by antizyme. Results: A novel reporter gene approach was established to monitor translational frameshifting of C. elegans antizyme in vivo. A handful of other antizyme targets have been proposed, including the transcriptional regulator of the bone morphogenetic pathway SMAD-1 and the mitosis/cell cycle regulatory proteins Cyclin D1 and Aurora A [5,6,7] These have been questioned recently, restricting antizyme function solely to the cellular polyamine metabolism [8]. We have found that antizyme levels are enhanced under food deprivation and other stressful conditions, including heat, UV exposure, and oxidative stress Most remarkably, this stress-induced increase in antizyme level occurs even in the absence of polyamine synthesis and independent of an increment in the intracellular polyamine concentrations. Monitoring intra- and extracellular physiological conditions, the TORC-1 pathway controls cell functions such as protein synthesis, autophagy, cell growth, and cell proliferation It is involved in aging and stress response [30, 31]. Our findings suggest that the role of C. elegans antizyme is not limited to polyamine regulation but is extended to cellular protein homeostasis under stressful conditions
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