Regulation of fat mass and obesity-associated (FTO) function by protein ubiquitination

Widagdo J, Zhu T and Anggono V

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia.

The fat mass and obesity-associated (FTO) protein is an RNA demethylase that dynamically reverses the methylation of adenosine base at the N6 position (m6A). Genetic polymorphisms in FTO gene have been strongly associated with obesity in humans. The cellular level of FTO is tightly regulated, with alterations in its expression influencing energy metabolism, food intake and body weight. More recently, I have discovered a role for FTO in regulating m6A dynamics and memory consolidation in the mouse prefrontal cortex (Widagdo et al., J. Neurosci., 2016). Accumulating evidence has demonstrated the physiological importance of FTO proteostasis, however, the cellular mechanism underlying FTO protein turnover remains unknown. Here, I will present evidence that FTO undergoes post-translational ubiquitination on the evolutionary conserved Lys-216. CRISPR/Cas-9-mediated knock-in cells harboring the ubiquitin-deficient K216R mutation displayed a slower rate of FTO turnover, resulting in an increase in the level of FTO as well as enhanced phosphorylation of the ribosomal S6 kinase. Surprisingly, K216R mutation reduced the level of nuclear FTO and completely abolished the nuclear translocation of FTO in response to amino acid starvation. Collectively, my results reveal the functional importance of ubiquitination in controlling FTO expression and localization, which may be crucial for determining body mass and composition, as well as synaptic plasticity, learning and memory.