Nardone et al. elucidate the mechanism of the midnolin-proteasome pathway, showing how midnolin achieves nuclear substrate selection and how established proteasomal components are repurposed to enable a unique form of ubiquitination-independent proteolysis. This study also unveils midnolin downregulation as a key driver of multiple myeloma through the aberrant stabilization of IRF4.

The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome compl...