Molecular mechanisms in rare proteasomopathies

Proteasomopathies comprise rare interferonopathy-related syndromes caused by genetic defects in proteasomal subunits or their assembly factors resulting in failed proteasome biogenesis and/or function. The concomitant proteasome impairment leads to imbalanced protein homeostasis by dysfunctional ubiquitin-mediated protein degradation. Two distinct clinical phenotypes have been characterised in proteasomopathies so far: (i) proteasome-associated autoinflammatory syndromes and (ii) proteasome-associated neurodevelopmental disorders. Despite these differences, both syndromes show molecular similarities with protein aggregation, activated stress responses, metabolic imbalance and dysregulated type I interferon signalling. Diagnostics and clinical management are complex even if genetic information is available. Here, we integrate the current knowledge of mammalian proteasome biogenesis with structural modelling of known proteasomopathy-causing variants and discuss the innovations of structural modelling to accelerate diagnosis.