Tripeptidyl-peptidase II: Update on an oldie that still counts

The huge exopeptidase, tripeptidyl-peptidase II (TPP II), appears to be involved in a large number of important biological processes. It is present in the cytosol of most eukaryotic cells, where it removes tripeptides from free amino termini of longer peptides through a 'molecular ruler mechanism'. Its main role appears to be general protein degradation, together with the proteasome. The activity is increased by stress, such as during starvation and muscle wasting, and in tumour cells. Overexpression of TPP II leads to accelerated cell growth, genetic instability and resistance to apoptosis, whereas inhibition or down-regulation of TPP II renders cells sensitive to apoptosis. Although it seems that humans can survive without TPP II, it is not without consequences. Recently, patients with loss-of-function mutations in the TPP2 gene have been identified. They suffer from autoimmunity leading to leukopenia and other consequences. Furthermore, a missense mutation in the TPP2 gene is associated with a sterile brain inflammation condition mimicking multiple sclerosis. This review will summarise what is known today regarding the activity and structure of this very large enzyme complex, and its potential function in various cellular processes. It is clear that more research is needed to identify natural substrates and/or interaction partners of TPP II, which can explain the observed effects in different cellular contexts.