Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honoré N, Doubeikovsky A, Duprez E, Pandolfi P P, Puvion E, Freemont P, de Thé H
Centre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N degrees 11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France.
J Exp Med. 2001 Jun 18;193(12):1361-71. doi: 10.1084/jem.193.12.1361.
Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) alpha expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARalpha and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARalpha degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.
早幼粒细胞白血病（PML）是核基质结构域即PML核体（NBs）的组织者，在细胞凋亡控制中发挥着一定作用。在急性早幼粒细胞白血病中，PML/维甲酸受体（RAR）α的表达会破坏核体，但维甲酸或三氧化二砷（As2O3）等疗法可使其恢复。PML与泛素相关肽SUMO-1共轭，这一过程会被As2O3增强，并被认为可将PML靶向至核基质。我们证明，As2O3会触发蛋白酶体依赖性的PML和PML/RARα降解，且这一过程需要PML中的一个特定SUMO化位点K160。PML的SUMO化对于其由As2O3诱导的基质靶向和初级核聚集体的形成并非必需，但对于次级壳样核体的形成却是必需的。有趣的是，只有这些成熟的核体含有11S蛋白酶体成分，在As2O3暴露时这些成分会进一步被招募。SUMO化的PML对蛋白酶体的招募可能是PML-K160R无法被降解的原因。因此，通过研究As2O3诱导的PML/RARα降解的基础，我们发现PML的SUMO化直接或间接促进了其分解代谢，这表明成熟的核体可能是核内蛋白水解的位点，并为在病毒感染或转化中发现的核体改变提供了新的见解。
