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Professor Jun Cui and Jian Ren’s joint group discovered the important regulatory function of m6A modification in autophagy

Last updated :2018-08-17

Source: School of Life Sciences
Written by: School of Life Sciences
Edited by: Wang Dongmei

Recently, researchers of Prof. Jun Cui and Jian Ren’s joint group from School of Life Sciences, Sun Yat-sen University published a paper titled as ‘m6A RNA modification controls autophagy through upregulating ULK1 protein abundance’ on Cell Research, reported that m6A RNA modification played a critical role in autophagy for the first time. This report revealed that FTO, an m6A ‘eraser’ of RNA methylation, inhibited the degradation of ULK1 protein through cleaving the m6A modification in the 3′-untranslated region (3′-UTR) of ULK1 transcripts, thus promoting the autophagy flux. Shouheng Jin, the associate research fellow, Xiya Zhang, the post-doctor and Yanyan Miao, the associate research fellow from School of Life Sciences were the co-first authors of this research. Prof. Jun Cui and Jian Ren from School of Life Sciences were the correspondence authors of this paper.

Under autophagy initiation conditions, FTO demethylated ULK1 transcripts by suppressing their YTHDF2-dependent degradation, thus up-regulating ULK1 protein abundance and promoting autophagy flux.
 
In this work, the researchers identified that FTO functioned as positive factor of autophagy via up-regulating the protein level of ULK1. Through employing the newest m6A-seq technology, the researcher found three distributions of m6A in the 3′-UTR of ULK1 transcript and further confirmed that FTO could demethylate the m6A modification, thereby promoting the protein abundance of ULK1. m6A modification is the degradation signal of ULK1 transcripts. Upon autophagy initiation, FTO could significantly remove the m6A modification of the 3′-UTR of ULK1 mRNA, further suppressing the recognition and degradation of ULK1 transcripts by YTHDF2, thus prolonging the half-life time of ULK1 transcripts and facilitating autophagy process (see image above).

Autophagy is a fundamental cellular process in eukaryotic cells, which sequesters cytoplasmic material within double-membraned autophagosomes and leads to degradation and recycling of the engulfed substrates, such as toxic protein aggregates, dysfunction and useless organelles and invading pathogens. It is essential for most biological processes and is widely associated with various physiological and pathological process, including tumor metabolism and neurodegenerative disorder, cardiovascular disease and high blood pressure. Therefore, it is important to discover the mechanism of autophagy initiation and regulation. The research reveals a crosstalk of mRNA m6A modification and autophagy for the first time, which broadens the multilayer regulation of autophagy and expands new insights to understand m6A modification in life processes.

This work was supported by National Natural Science Foundation of China, National Key Basic Research Program of China, Science and Technology Planning Project of Guangzhou, China, and China Postdoctoral Science Foundation.