Nuclear p62 condensates stabilize the promyelocytic leukemia nuclear bodies by sequestering their ubiquitin ligase RNF4

• 成果类型: Article
• 署名作者: Fu, Afu; Luo, Zhiwen; Ziv, Tamar; Bi, Xinyu; Lulu-Shimron, Chen; Cohen-Kaplan, Victoria; Ciechanover, Aaron
• 署名单位: Technion Israel Institute of Technology; Rappaport Faculty of Medicine; Technion Israel Institute of Technology; Chinese Academy of Medical Sciences - Peking Union Medical College; Cancer Institute & Hospital - CAMS; Peking Union Medical College; Technion Israel Institute of Technology; Technion Israel Institute of Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9281
• DOI: 10.1073/pnas.2414377121
• 发表日期: 2024-10-17
• 关键词: liquid phase-separation; pml

摘要

Liquid-liquid phase separation has emerged as a crucial mechanism driving the formation of membraneless biomolecular condensates, which play important roles in numerous cellular processes. These condensates, found both in the nucleus and cytoplasm, are formed through multivalent, low- affinity interactions between various molecules. P62- containing condensates serve, among other functions, as proteolytic hubs for the ubiquitin-proteasome system. In this study, we investigated the dynamic interplay between nuclear p62 condensates and promyelocytic nuclear bodies (PML-NBs). We show that p62 condensates stabilize PML-NBs under both basal conditions and following exposure to arsenic trioxide which stimulates their degradation. We further show that this effect on the stability of PML-NBs is due to sequestration of their ubiquitin E3 ligase RNF4 in the p62 condensates with subsequent rapid degradation of the ligase. The sequestration of the ligase is made possible by association between the proline-rich domain of the PML protein and the PB1 domain of p62, which results in the formation of a PML-NB shell around the p62 condensates. Importantly, these hybrid structures do not undergo fusion and mixing of their contents which leaves unsolved the mechanism of sequestration of RNF4 in the condensates. These findings suggest an additional possible mechanism of PML-NB as a tumor suppressor which is mediated via interactions between different biomolecular condensates.