Alongside the discovery and molecular characterisation of components of the Met1-Ub machinery, numerous genetic mouse models together with the identification of germline mutations in humans affecting the Met1-Ub machinery has greatly advanced our knowledge about the physiological and pathophysiological role of Met1-Ub: hypomorphic mutations in HOIP or truncating mutations in HOIL-1 cause a complex clinical pathology characterised by autoinflammation, immunodeficiency and muscular amylopectinosis [36–38]. This evidence concerns the gene GZMM and Immunodeficiency.