To date, five human coronaviruses (CoV) have been identified including the common human respiratory pathogen NL63, that has been shown to be associated with both upper and lower respiratory tract disease such as bronchiolitis and croup.The prevalence of NL63 infections is illustrated by epidemiological studies reporting that NL63 CoV was detected in 0.3-10% of clinical specimens from both adults and infants diagnosed with respiratory tract diseases. The NL63 genome encodes two papain like proteases, PLP1 and PLP2. PLP2 is a dual specificity isopeptidase with both deubiquitylase and deISGylase activity. PLP2 cleaves Ub-PLA2 and ISG15-PLA2 with high and moderate efficiency respectively.