Polynucleotide phosphorylase: Not merely an RNase but a pivotal post-transcriptional regulator

Almost 60 years ago, Severo Ochoa was awarded the Nobel Prize in Physiology or Medicine for his discovery of the enzymatic synthesis of RNA by polynucleotide phosphorylase (PNPase). Although this discovery provided an important tool for deciphering the genetic code, subsequent work revealed that the predominant function of PNPase in bacteria and eukaryotes is catalyzing the reverse reaction, i.e., the release of ribonucleotides from RNA. PNPase has a crucial role in RNA metabolism in bacteria and eukaryotes mainly through its roles in processing and degrading RNAs, but additional functions in RNA metabolism have recently been reported for this enzyme. Here, we discuss these established and noncanonical functions for PNPase and the possibility that the major impact of PNPase on cell physiology is through its unorthodox roles.
Author summary Widely distributed among bacteria and eukaryotes, including humans, polynucleotide phosphorylase (PNPase) is a critical enzyme in RNA metabolism that functions in most organisms as a 3ʹ to 5ʹ exoribonuclease. In bacteria, inactivation of the gene encoding PNPase results in a wide range of consequences, including impaired growth, diminished stress responses, and loss of virulence. In mammals, PNPase has an essential role in mitochondrial function. Mutations in the gene encoding the human PNPase (hPNPase) that reduce its activity can lead to hereditary hearing loss, encephalomyopathy, severe axonal neuropathy, delayed myelination, and Leigh syndrome. In this review, we highlight both the canonical and unorthodox activities that have been reported for PNPase. Specifically, we examine its role in bacterial mRNA and rRNA decay, RNA processing, and small regulatory RNA (sRNA) degradation and stabilization. Furthermore, we explore the recently reported findings on the function of hPNPase in mitochondrial RNA import and degradation and cytoplasmic mRNA and noncoding RNA decay. Despite being discovered more than six decades ago, we are still only beginning to grasp the breadth of mechanisms by which the enzymatic activities of PNPase contribute to cellular and organismal physiology.