Mechanisms of autophagy control through micrornas under cellular stress
Öztürk, Deniz Gülfem (2019) Mechanisms of autophagy control through micrornas under cellular stress. [Thesis]
Macroautophagy (autophagy) is an evolutionarily conserved stress response mechanism that is necessary for the maintenance of cellular homeostasis. Autophagic activity in cells is regulated by various upstream signaling pathways including mTOR. Stress-mediated inhibition of mTOR complex 1 (mTORC1) results in the nuclear translocation of the TFE/MITF family of transcriptional factors, and triggers an autophagy- and lysosomal-related gene transcription program. In this thesis work, we introduce a specific and rate-limiting role for MITF in autophagy regulation that requires transcriptional activation of MIR211. Under stress conditions including starvation and mTOR inhibition, a MITF-MIR211 axis constitutes a novel feedforward loop that controls autophagic activity in cells. Direct targeting and downregulation of mTORC2 binding partner RICTOR by MIR211 attenuated mTORC1 signal through AKTmediated crosstalk. Under these conditions, the transcription factor MITF translocated from cytosol to the nucleus, and amplified autophagic activity. All together, the outcome of this thesis is the identification of MITF-MIR211 axis as a novel autophagy amplification mechanism required for optimal autophagy activation under cellular stress conditions.
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