Tissue-specific regulation of 3′-nucleotide hydrolysis and nucleolar architecture

Abstract

Sulfur is an essential micronutrient involved in diverse cellular functions ranging from the control of intracellular redox states to electron transport. Eukaryotes incorporate sulfur by metabolizing inorganic sulfate into the universal sulfur donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS). Sulfotransferases then catalyze the donation of the activated sulfur from PAPS to a broad range of acceptors including xenobiotic small molecules and extracellular proteoglycans while also generating the byproduct 3'-phosphoadenosine 5'-phosphate (PAP). In mammals, PAP is regulated by two related 3'-nucleotidases, Golgi-resident PAP phosphatase (gPAPP) and cytoplasmic bisphosphate 3'-nucleotidase 1 (Bpnt1), which hydrolyze PAP to 5'-AMP and whose inactivation results in severe physiological defects. Loss of Bpnt1 in mice leads to the accumulation of PAP in the liver, aberrant nucleolar architecture, and liver failure, all of which can be rescued by genetically repressing PAPS synthesis. Yet interestingly, Bpnt1 protein is expressed at high levels in a majority of tissues, suggesting that additional tissues might also be affected. To investigate this possibility, we closely examined the expression of Bpnt1 protein, accumulation of PAP, and appearance of dysmorphic nucleoli in wild-type and Bpnt1(-/-) mice. Surprisingly, we found that while Bpnt1 protein is widely expressed, only the liver, duodenum, and kidneys contain high levels of PAP and nucleolar reorganization. We hypothesize that these tissues share commonalities such as being highly polarized and situated at the interfaces of fluid reservoirs that might enhance their susceptibility to loss of Bpnt1. These studies highlight the importance of PAP metabolism in extrahepatic tissues and provide a framework for future investigations into the function of Bpnt1 in the kidney and small intestine.