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

• 成果类型: Article
• 署名作者: Gu, Xin; Nardone, Christopher; Kamitaki, Nolan; Mao, Aoyue; Elledge, Stephen J.; Greenberg, Michael E.
• 署名单位: Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13905
• DOI: 10.1126/science.adh5021
• 发表日期: 2023-08-25
• 页码: 849-+
• 关键词: ornithine-decarboxylase; delta-fosb; transcription; domains; chain; irf4; STABILITY; complex; proteolysis; propensity

摘要

Cells use ubiquitin to mark proteins for proteasomal degradation. Although 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 a helix, used its Catch domain to bind a region within substrates that can form a beta 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.