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RING tetramerization is required for nuclear body biogenesis and PML sumoylation

Pengran Wang, Shirine Benhenda, Haiyan Wu, Valérie Lallemand-Breitenbach, Tao Zhen, Florence Jollivet, Laurent Peres, Yuwen Li, Sai-Juan Chen, Zhu Chen (), Hugues Thé () and Guoyu Meng ()
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Pengran Wang: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Shirine Benhenda: University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC
Haiyan Wu: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Valérie Lallemand-Breitenbach: University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC
Tao Zhen: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Florence Jollivet: University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC
Laurent Peres: University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC
Yuwen Li: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Sai-Juan Chen: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Zhu Chen: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Hugues Thé: University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC
Guoyu Meng: Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03498-0

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