Aryan Fardin, Detrés Diego, Luo Claire C, Kim Skylar X, Shah Arish N, Bartusel Michaela, Flynn Ryan A, Calo Eliezer
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Mol Cell. 2023 Dec 7;83(23):4413-4423.e10. doi: 10.1016/j.molcel.2023.10.031. Epub 2023 Nov 17.
DEAD-box ATPases are major regulators of biomolecular condensates and orchestrate diverse biochemical processes that are critical for the functioning of cells. How DEAD-box proteins are selectively recruited to their respective biomolecular condensates is unknown. We explored this in the context of the nucleolus and DEAD-box protein DDX21. We find that the pH of the nucleolus is intricately linked to the transcriptional activity of the organelle and facilitates the recruitment and condensation of DDX21. We identify an evolutionarily conserved feature of the C terminus of DDX21 responsible for nucleolar localization. This domain is essential for zebrafish development, and its intrinsically disordered and isoelectric properties are necessary and sufficient for the ability of DDX21 to respond to changes in pH and form condensates. Molecularly, the enzymatic activities of poly(ADP-ribose) polymerases contribute to maintaining the nucleolar pH and, consequently, DDX21 recruitment and nucleolar partitioning. These observations reveal an activity-dependent physicochemical mechanism for the selective recruitment of biochemical activities to biomolecular condensates.
DEAD盒ATP酶是生物分子凝聚物的主要调节因子，协调对细胞功能至关重要的各种生化过程。目前尚不清楚DEAD盒蛋白是如何被选择性募集到其各自的生物分子凝聚物中的。我们在核仁及DEAD盒蛋白DDX21的背景下对此进行了探究。我们发现，核仁的pH值与该细胞器的转录活性密切相关，并促进DDX21的募集和凝聚。我们鉴定出DDX21 C末端负责核仁定位的一个进化保守特征。该结构域对斑马鱼发育至关重要，其固有无序和等电特性对于DDX21响应pH值变化并形成凝聚物的能力而言是必要且充分的。在分子层面，聚（ADP-核糖）聚合酶的酶活性有助于维持核仁pH值，进而促进DDX21的募集和核仁分配。这些观察结果揭示了一种将生化活性选择性募集到生物分子凝聚物的活性依赖性物理化学机制。
