RNF126 writes a non‑canonical ubiquitin code on midnolin to tune protein stabilityOA
Midnolin(MIDN)is a newly recognized master regulator that drives ubiquitin‑independent proteasomal degradation,yet the mechanisms governing its own turnover remain enigmatic.Here,we demonstrate that MIDN is ubiquitinated and identify RNF126 as the cognate E3 ligase.RNF126 physically associates with MIDN and catalyzes its ubiquitination,and mass spectrometry mapping reveals that this process occurs primarily at non‑canonical cysteine,serine,and threonine residues(C230,C236,S237,T239,and S241)rather than at lysine residues.This non‑classical ubiquitination targets MIDN for 26S‑proteasomal degradation.In vivo dissection of the RNF126‑MIDN axis shows that it governs EGR1 abundance and,consequently,the tumor‑suppressor proteins PTEN and p53,thereby restraining the progression of testicular germ‑cell tumors(TGCTs).Our findings reveal an unappreciated layer of MIDN regulation and identify the RNF126‑MIDN ubiquitination cascade as a potential therapeutic vulnerability in TGCTs and related malignancies.
Yun Yang;Jin Ren;Xiang Qiu;Yanlin Liu;Shilin Yuan;Ronggui Hu;Zhixiong Xia;Chuanyin Li
School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China State Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China Department of Colorectal Surgery and Oncology(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China Center for Medical Research and Innovation in Digestive System Tumors,Ministry of Education,Hangzhou 31009,ChinaState Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,ChinaState Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China Department of Colorectal Surgery and Oncology(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China Center for Medical Research and Innovation in Digestive System Tumors,Ministry of Education,Hangzhou 31009,ChinaState Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China Department of Colorectal Surgery and Oncology(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China Center for Medical Research and Innovation in Digestive System Tumors,Ministry of Education,Hangzhou 31009,ChinaState Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,ChinaSchool of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China State Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China Department of Colorectal Surgery and Oncology(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China Center for Medical Research and Innovation in Digestive System Tumors,Ministry of Education,Hangzhou 31009,ChinaSchool of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China Department of Colorectal Surgery and Oncology(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China Center for Medical Research and Innovation in Digestive System Tumors,Ministry of Education,Hangzhou 31009,ChinaState Key Laboratory of Molecular Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China Department of Colorectal Surgery and Oncology(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education,Key Laboratory of Molecular Biology in Medical Sciences,Zhejiang Province,China),the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China Center for Medical Research and Innovation in Digestive System Tumors,Ministry of Education,Hangzhou 31009,China
医药卫生
MIDNRNF126non‑lysine ubiquitinationproteasomal degradationEGR1
《Acta Biochimica et Biophysica Sinica》 2026 (5)
P.1170-1178,9
funded by the grants from the National Natural Science Foundation of China(Nos.92253302,82200667,82304563 and 31900804)the National Science and Technology Innovation 2030 Major Project of China(No.2021ZD0203900)the Ministry of Science and Technology of China(No.2019YFA0802103)the Department of Science and Technology of Zhejiang Province(No.2021C03104)the Shenzhen‑Hong Kong Institute of Brain Science(No.NYKFKT2019006).
评论