Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Mol Cell. 2021 Mar 4;81(5):1013-1026.e11. doi: 10.1016/j.molcel.2021.01.016. Epub 2021 Feb 5.
In response to stress, human cells coordinately downregulate transcription and translation of housekeeping genes. To downregulate transcription, the negative elongation factor (NELF) is recruited to gene promoters impairing RNA polymerase II elongation. Here we report that NELF rapidly forms nuclear condensates upon stress in human cells. Condensate formation requires NELF dephosphorylation and SUMOylation induced by stress. The intrinsically disordered region (IDR) in NELFA is necessary for nuclear NELF condensation and can be functionally replaced by the IDR of FUS or EWSR1 protein. We find that biomolecular condensation facilitates enhanced recruitment of NELF to promoters upon stress to drive transcriptional downregulation. Importantly, NELF condensation is required for cellular viability under stressful conditions. We propose that stress-induced NELF condensates reported here are nuclear counterparts of cytosolic stress granules. These two stress-inducible condensates may drive the coordinated downregulation of transcription and translation, likely forming a critical node of the stress survival strategy.
为应对压力，人体细胞会协调地下调管家基因的转录和翻译。为了下调转录，负延伸因子（NELF）被招募到基因启动子处，从而损害 RNA 聚合酶 II 的延伸。在此，我们报告称，NELF 在人细胞受到压力时会迅速形成核凝聚体。凝聚体的形成需要 NELF 在压力下的去磷酸化和 SUMO 化。NELFA 中的无规则结构域（IDR）对于核 NELF 凝聚是必需的，并且可以被 FUS 或 EWSR1 蛋白的 IDR 功能替代。我们发现，生物分子凝聚促进了 NELF 在应激时更有效地招募到启动子，从而驱动转录下调。重要的是，NELF 凝聚对于细胞在应激条件下的存活是必需的。我们提出，这里报道的应激诱导的 NELF 凝聚体是胞质应激颗粒的核对应物。这两种应激诱导的凝聚体可能会驱动转录和翻译的协调下调，可能形成应激生存策略的关键节点。
