Autophagy is closely related to neurodegenerative diseases, cardiovascular diseases and tumors. The autophagy substrates are fused with lysosomes and eventually degraded by acidic hydrolysates in lysosomes, so the biogenesis of lysosome is crucial in the process of autophagy.

In recent years, many studies have found that the miRNA can regulate autophagy process through targeting different autophagy-lysosome related genes, but miRNAs were found being located almost in the cytoplasm through the classical molecular mechanism of post-transcriptional regulation. Nevertheless, whether miRNA can regulate autophagy in the nucleus, how to regulate the autophagy process and the molecular mechanism are still unclear.

After the publication of an article on Oncogene, the research team led by Professor REN Jin, director of the Center for Drug Safety Evaluation and Research (CDSER), published recently a study entitled "Nuclear miR-30b-5p suppresses TFEB-mediated Lysosomal Biogenesis and Autophagy" in Cell Death & Differentiation, a journal published by Nature Publishing Group.

Through RNA-seq, protein spectrum analysis, CRISPR/Cas9 knock out systems and a series of new methods, the study explored the molecular mechanisms, as well as the function of miR-30b-5p in vivo and in vitro, the results showed that miR-30b-5p locates in the nucleus and binds to the autophagy-lysosome related gene promoter region CLEAR element, occupies the transcription factor TFEB (the key transcription factors regulates lysosomal biogenesis and the process of autophagy) binding sites and inhibits TFEB transcriptional activity, thus inhibits the lysosomal biogenesis and autophagy.

This study proved that the mature form of miRNA enters the nucleus via non-classic gene transcription regulation, revealed its roles in the new molecular mechanism of the interaction among the cis-element and transcription factors. Meanwhile, researchers illuminated the significant role of miRNA in autophagy, further expanded the molecular mechanism of non-coding RNA regulating the function of transcriptional factor. These findings also providing new hints and new strategies for the treatment of autophagy-related diseases.

This research is the original achievement from Dr. TAO Zhouteng, who joined CDSER after graduation in 2016, and Dr. Guo Huijie. It is also a new achievement obtained by CDSER based on many years of research on non-coding RNA. Prof. HUANG Ruimin participated also in the study. The research was supported by the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", the National Natural Science Foundation of China.

Article link: https://www.nature.com/articles/s41418-020-0602-4

miR-30b-5p locates in the nucleus and could inhibit the binding of TFEB to the promoters of target genes.

miR-30b-5p suppresses the lysosomal biogenesis while knocking out miR-30b-5p promotes the lysosomal biogenesis significantly.

Schematic diagram showing that nuclear miR-30b-5p inhibits the transcriptional activity of TFEB by binding to its binding sites to suppress the autophagy–lysosomal process.

Contact:
Prof. REN Jin
Email: jren@cdser.simm.ac.cn

(Credit: TAO Zhouteng)