Lysyl tRNA synthetase – a possible non conventional role of a translational factor in autophagy regulation

We have previously described a signal transduction pathway in which the initial step is the release of Lysyl tRNA synthetase (KARS) from the cytoplasmic multisynthetase complex following its phosphorylation, and its translocation to the nucleus. We demonstrated that this modified protein can not acetylate lysyl but has the capacity to produce AP4A (a putative second messenger) and bind to the transcription factor MITF and activate it.

MITF is a member of a transcription factor family MiT (MITF TFEbTFE3 TFEc) which are known to be critically important in transcriptional control of of autophagy genes. Since LysRS has a critical role in translational control we hypothesized that it may also at its "moonlighting "role influence autophagy which is a process that provides much of the aminoacids needed for translation in metabolically stressed cells.

We used retrovirally transduced lung cancer cells which inducibly express either LysRS with a psuedophosphorylated site (LysRSD) or a non phosphorylated site (LysRSA). Our initial results demonstrate that both forms of Lysyl trna synthetase may bind MITF and also TFEB and TFE3. There is opposite effect of LysRSD vs LysRSA on autophagy flux in lung cancer cells which depends upon the metabolic state of the cells. Interestingly we found that forms of LysRS bind the transcription factors already in the cytoplasm and may influence the translocation of those factors to the nucleus .

Further experiments are required to define the physiological importance of moonlighting lysRS effects on autophagy in cancer cells.