The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation

Cells use ubiquitin to mark proteins for proteasomal degradation. While the proteasome also eliminates proteins that are not ubiquitinated, how this occurs mechanistically is unclear. Here we found that midnolin promoted the destruction of many nuclear proteins including transcription factors encoded by the immediate-early-genes. Diverse stimuli induced midnolin and its overexpression was sufficient to cause the degradation of its targets by a mechanism that did not require ubiquitination. Instead, midnolin associated with the proteasome via an α helix, employed its Catch domain to bind a region within substrates that can form a β strand, and used a ubiquitin-like domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation.