RING tetramerization is required for nuclear body biogenesis and PML sumoylation

• Published in: Nature communications Vol. 9; no. 1; pp. 1277 - 10
• Main Authors: Wang, Pengran, Benhenda, Shirine, Wu, Haiyan, Lallemand-Breitenbach, Valérie, Zhen, Tao, Jollivet, Florence, Peres, Laurent, Li, Yuwen, Chen, Sai-Juan, Chen, Zhu, de Thé, Hugues, Meng, Guoyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 13/106; 13/109; 13/31; 14/19; 14/35; 38/70; 631/337/458/538; 631/67/1990/283/1897; 64/60; 82/1; 82/16; 82/29; 82/80; 82/83; Acute promyeloid leukemia; Animals; Arsenic; Binding sites; Biochemistry, Molecular Biology; Biosynthesis; Cancer; Cell Line; Cellular Biology; Crystal structure; Crystallography; Crystallography, X-Ray; Dimerization; Enzymes; Genomics; Hematology; Humanities and Social Sciences; Humans; In vivo methods and tests; Laboratories; Leukemia; Leukemia, Promyelocytic, Acute - pathology; Leukemogenesis; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Multiprotein Complexes - metabolism; Mutants; Mutation; Nuclear Proteins - metabolism; Post-translation; Promyelocytic Leukemia Protein - metabolism; Promyeloid leukemia; Protein Folding; Protein Multimerization; Protein Processing, Post-Translational; Scaffolding; Science; Science (multidisciplinary); Small angle X ray scattering; Small Ubiquitin-Related Modifier Proteins - metabolism; Subcellular Processes; SUMO protein; Sumoylation; Ubiquitin; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - metabolism; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03498-0

ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications. Promyelocytic leukemia protein (PML) is a scaffolding protein that organizes PML nuclear bodies. Here the authors present the tetrameric crystal structure of the PML RING domain and show that RING tetramerization is functionally important for nuclear body formation and PML sumoylation.