Midnolin-proteasome pathway; plus inhibitory receptor on T cells and more

Researchers at Harvard Medical School, including serial entrepreneur Stephen Elledge, showed in Science midnolin targets nuclear proteins for proteasomal degradation in a ubiquitination-independent manner.

The authors performed a global protein stability assay to assess changes in stability for about 12,000 human proteins simultaneously and found midnolin promoted degradation of proteins such as IRF4, NEUROD1, PAX8, GATA1 and other transcriptional regulators in the nucleus. Midnolin interacted with unstructured regions within substrates, functioning as mindolin degrons, using its “catch” domain, and promoted the degradation of catch-bound targets using its N-terminal ubiquitin-like domain. Midnolin could be utilized to create targeted degraders of nuclear proteins...