Overcoming the cytoplasmic retention of GDOWN1 modulates global transcription and facilitates stress adaptation
Author:
Zhu Zhanwu1ORCID,
Liu Jingjing1,
Feng Huan1,
Zhang Yanning1,
Huang Ruiqi2,
Pan Qiaochu2,
Nan Jing1,
Miao Ruidong1,
Cheng Bo13ORCID
Affiliation:
1. School of Life Sciences, Lanzhou University
2. Cuiying Honors College, Lanzhou University
3. Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University
Abstract
Dynamic regulation of transcription is crucial for the cellular responses to various environmental or developmental cues. Gdown1 is a ubiquitously expressed, RNA polymerase II (Pol II) interacting protein, essential for the embryonic development of metazoan. It tightly binds Pol II in vitro and competitively blocks the binding of TFIIF and possibly other transcriptional regulatory factors, yet its cellular functions and regulatory circuits remain unclear. Here, we show that human GDOWN1 strictly localizes in the cytoplasm of various types of somatic cells and exhibits a potent resistance to the imposed driving force for its nuclear localization. Combined with the genetic and microscope-based approaches, two types of the functionally coupled and evolutionally conserved localization regulatory motifs are identified, including the CRM1-dependent nucleus export signal (NES) and a novel Cytoplasmic Anchoring Signal (CAS) that mediates its retention outside of the nuclear pore complexes (NPC). Mutagenesis of CAS alleviates GDOWN1’s cytoplasmic retention, thus unlocks its nucleocytoplasmic shuttling properties, and the increased nuclear import and accumulation of GDOWN1 results in a drastic reduction of both Pol II and its associated global transcription levels. Importantly, the nuclear translocation of GDOWN1 occurs in response to the oxidative stresses, and the ablation of GDOWN1 significantly weakens the cellular tolerance. Collectively, our work uncovers the molecular basis of GDOWN1’s subcellular localization and a novel cellular strategy of modulating global transcription and stress-adaptation via controlling the nuclear translocation of GDOWN1.
Funder
The National Natural Science Foundation of China
The Gansu Provincial Outstanding Graduate Student "Innovation Star" project
The Gansu Provincial Outstanding Graduate Student "Innovation Star" Project
The Foundation of the Ministry of Education of China, the Fundamental Research Funds for the Central Universities
The Foundation of the Ministry of Education of China, Key Laboratory of Cell Activities and Stress Adaptations Grant
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献