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 modified by
ubiquitin, how this occurs mechanistically is unclear. We show
here that midnolin promotes the destruction of many nuclear proteins
including transcription factors encoded by
the immediate-early-genes. Diverse environmental
cues induce midnolin and its overexpression is sufficient to
cause the degradation of its targets by a mechanism, which, remarkably,
does not require ubiquitination. Instead, midnolin associates with the
proteasome via an alpha-helix, employs its Catch-domain to bind a region
within substrates that adopts a beta-strand conformation, and uses 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.