Protein degradation, the main hub in the regulation of cellular polyamines

Abstract

Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme in the biosynthesis of polyamines, low-molecular-mass aliphatic polycations that are ubiquitously present in all living cells and are essential for fundamental cellular processes. Most cellular polyamines are bound, whereas the free pools, which regulate cellular functions, are subjected to tight regulation. The regulation of the free polyamine pools is manifested by modulation of their synthesis, catabolism, uptake and excretion. A central element that enables this regulation is the rapid degradation of key enzymes and regulators of these processes, particularly that of ODC. ODC degradation is part of an autoregulatory circuit that responds to the intracellular level of the free polyamines. The driving force of this regulatory circuit is a protein termed antizyme (Az). Az stimulates the degradation of ODC and inhibits polyamine uptake. Az acts as a sensor of the free intracellular polyamine pools as it is expressed via a polyamine-stimulated ribosomal frameshifting. Az binds to monomeric ODC subunits to prevent their reassociation into active homodimers and facilitates their ubiquitin-independent degradation by the 26S proteasome. In addition, through a yet unidentified mechanism, Az inhibits polyamine uptake. Interestingly, a protein, termed antizyme inhibitor (AzI) that is highly homologous with ODC, but retains no ornithine decarboxylating activity, seems to regulate cellular polyamines through its ability to negate Az. Overall, the degradation of ODC is a net result of interactions with regulatory proteins and possession of signals that mediate its ubiquitin-independent recognition by the proteasome.