Unmask the roles of Mask as a mTOR-independent Autophagy-Promoting Factor

Unmask the roles of Mask as a mTOR-independent Autophagy-Promoting Factor Abstract Effective regulation of cell survival is crucial for organisms to respond and adapt to various challenges. Autophagy, a conserved and genetically controlled process, plays a vital role in providing cells with means to weather diverse physiological stresses and ensure survive. While mTOR pathways have traditionally been recognized as central regulators of autophagy, recent discoveries suggest the existence of mTOR-independent mechanisms. Our research in flies has identified Mask, a conserved Ankyrin repeats and KH domain- containing protein, as a novel autophagy-promoting factor independent of the mTOR pathway. We found that Mask’s functions in fly larval muscles are both necessary and sufficient for promoting autophagic progression. Furthermore, Mask's role in promoting autophagy in neurons has shown various beneficial effects at the organism level. Upregulation of Mask and its mammalian homolog effectively alleviate neuronal degeneration in flies and mice, respectively. Most remarkably, increasing Mask levels in specific subsets of dopaminergic neurons extends the lifespan of flies by up to 50%. To further understand Mask’s molecular action, we took the BioID method to identify a list of putative in vivo Mask-interacting proteins ranging from microtubule-associated proteins to stress granule-associated RNA binding proteins. Our published and ongoing research suggests that Mask may execute its actions by modulating parallel pathways, including microtubule dynamics, lysosomal function, and RNA processing and translation, in a cell-type-specific manner. Our primary research goals are to 1) decipher the molecular actions of Mask by investigating its interactions with its binding-partners; and 2) Unravel Mask's influence on RNA splicing, metabolism, and translation using a combination of a candidate approach and unbiased RNA profiling and cell-type-specific nascent proteome approaches. These studies aim to clarify whether Mask's effects on microtubule dynamics and RNA-based regulations cooperate or act independently to impact cell survival. We also seek to understand how these novel mechanisms intersect with known pathways governing cellular stress response, homeostasis, and survival. Ultimately, this research holds the potential to unravel new mechanisms of autophagy and cell survival regulation, paving the way for future therapeutic interventions.