Abstract
Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.
Highlights
Autophagy is the process that enables self-clearance of potentially damaging protein aggregates, dysfunctional organelles, or entire cells, and as such it is one of the most significant regulatory processes that ensures healthy functioning of cells [1,2]
We manually curated the role of the selected 225 autophagy modulators based on data/reports in the literature, and we classified them into three functional categories: activators (n = 174), inhibitors (n = 31), and dual-modulators (n = 20)
We examined to what extent the autophagy modulators within each group share structural and functional similarities
Summary
Autophagy is the process that enables self-clearance of potentially damaging protein aggregates, dysfunctional organelles (e.g., mitochondria by mitophagy), or entire cells, and as such it is one of the most significant regulatory processes that ensures healthy functioning of cells [1,2]. E.g., by stress stimuli such as starvation, a cascade of reactions are triggered that lead to the formation of a double-membrane-bound vesicle called an autophagosome [5], which encapsulates the cytoplasmic aggregates or dysfunctional organelles. MTOR, a serine/threonine kinase, is a downstream regulator of the phosphoinositide 3-kinase (PI3K) pathway. It suppresses autophagy induction by inhibiting the activation of the UNC-51-like autophagy activating kinase (ULK) complex [8]. The complex of activated ULK1 with autophagy related 1 (Atg1) protein, Atg1-ULK, would otherwise receive signals on cellular nutrient status and recruit downstream autophagy-related (ATG) proteins to the autophagosome formation site, initiating an autophagic response [9]. The complex of activated ULK1 with autophagy related 1 (Atg1) protein, Atg1-ULK, would otherwise receive signals on cellular nutrient status and recruit downstream autophagy-related (ATG) proteins to the autophagosome formation site, initiating an autophagic response [9]. mTOR further acts as a negative regulator of autophagy by preventing the general expression of lysosomal and autophagy genes through phosphorylating transcription factor EB (TFEB) [7,8]
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