THOC4 regulates energy homeostasis by stabilizing TFEB mRNA during prolonged starvation
THOC4 regulates energy homeostasis by stabilizing TFEB mRNA during prolonged starvation
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DOI：
10.1242/jcs.248203
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发表时间：
2021-02
影响因子：
4
通讯作者：
Toshiharu Fujita;Sayaka Kubo;Tatsuya Shioda;Ayaka Tokumura;S. Minami;Megumi Tsuchiya;Y. Isaka;Hidesato Ogawa;Maho Hamasaki;Li Yu;T. Yoshimori;Shuhei Nakamura
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作者：
Toshiharu Fujita;Sayaka Kubo;Tatsuya Shioda;Ayaka Tokumura;S. Minami;Megumi Tsuchiya;Y. Isaka;Hidesato Ogawa;Maho Hamasaki;Li Yu;T. Yoshimori;Shuhei Nakamura
TFEB是一种碱性螺旋-环-螺旋转录因子，是细胞自噬、溶酶体生物合成和脂质过氧化的主要调节因子。与TFEB的翻译后调节相比，TFEB mRNA稳定性的调节仍然相对未表征。在这项研究中，我们确定了mRNA结合蛋白THOC 4作为TFEB的一种新的调节剂。在哺乳动物细胞中，siRNA介导的TH 0 C4敲低降低TFEB蛋白水平的程度大于其他bHLH转录因子。TH 0 C4与TFEB mRNA结合，并在转录后通过维持聚腺苷酸尾长度来稳定TFEB mRNA。我们进一步发现，这种调控模式在秀丽隐杆线虫中是保守的，并且对于TFEB介导的脂质分解是必不可少的，在长时间的饥饿期间，TFEB介导的脂质分解变得过度。总之，我们的研究结果揭示了THOC 4对TFEB调节的额外层的存在，并为TFEB在介导自噬和脂质代谢中的功能提供了新的见解。突出显示的文章：mRNA结合蛋白THOC 4调节TFEB的mRNA稳定性，以维持长期饥饿期间的能量稳态。
ABSTRACT TFEB, a basic helix-loop-helix transcription factor, is a master regulator of autophagy, lysosome biogenesis and lipid catabolism. Compared to posttranslational regulation of TFEB, the regulation of TFEB mRNA stability remains relatively uncharacterized. In this study, we identified the mRNA-binding protein THOC4 as a novel regulator of TFEB. In mammalian cells, siRNA-mediated knockdown of THOC4 decreased the level of TFEB protein to a greater extent than other bHLH transcription factors. THOC4 bound to TFEB mRNA and stabilized it after transcription by maintaining poly(A) tail length. We further found that this mode of regulation was conserved in Caenorhabditis elegans and was essential for TFEB-mediated lipid breakdown, which becomes over-represented during prolonged starvation. Taken together, our findings reveal the presence of an additional layer of TFEB regulation by THOC4 and provide novel insights into the function of TFEB in mediating autophagy and lipid metabolism. Highlighted Article: The mRNA-binding protein THOC4 modulates mRNA stability of TFEB for the maintenance of energy homeostasis during prolonged starvation.