Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

Abstract

Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and autoimmunity. These findings have motivated the use of small-molecule probes to study how modulation of autophagy affects disease-associated phenotypes. Here, we describe the discovery of the small-molecule probe BRD5631 that is derived from diversity-oriented synthesis and enhances autophagy through an mTOR-independent pathway. We demonstrate that BRD5631 affects several cellular disease phenotypes previously linked to autophagy, including protein aggregation, cell survival, bacterial replication, and inflammatory cytokine production. BRD5631 can serve as a valuable tool for studying the role of autophagy in the context of cellular homeostasis and disease.high-throughput screening | autophagy | small-molecule probes | Crohn's disease

ER-stress mobilization of death-associated protein kinase-1–dependent xenophagy counteracts mitochondria stress–induced epithelial barrier dysfunction

“…Further, a cytoprotective effect of ATG16L1 in epithelial cells promoted mitochondrial homeostasis and prevented necroptosis (34). Collectively, these data suggest that the development of drugs that drive autophagy (35) or an appropriate UPR (ER stress) pathway would be of value in treating enteropathies (e.g. IBD) characterized by loss of epithelial barrier function -that is, uptake and passage of commensal bacteria, pathobionts and pathogens -due to perturbed mitochondrial function.…”

Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

“…Nevertheless, long-term treatment with mTOR inhibitors may not be sufficiently well tolerated in patients with chronic diseases such as UAKD. Efforts are currently underway to identify mTOR-independent mechanisms to enhance autophagy (92,93). In addition to strategies that inhibit downstream cell death mediators like TNF-α or activate endogenous autophagy programs to alleviate the cellular burden of misfolded protein accumulation, an emergent therapeutic approach to treating chronic states of ER stress and UPR activation, particularly in the field of neurodegeneration (94,95), has yielded several small-molecule modulators of components of the UPR itself.…”

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…These include (but are not limited to) the production of cAMP-elevating toxins ( Vibrio cholera and Bacillus anthracis ) 173 , the normalization of otherwise dwindling amino acid levels at the surface of bacterium-containing vacuoles ( S. Typhimurium) 174 , the deconjugation of microtubule-associated protein 1 light chain 3β ( MAP1LC3B ; also known as LC3) ( Legionella pneumophila ) 175 , the inactivation of GTPases that are required for normal vesicular trafficking ( Shigella flexneri and pathogenic Escherichia coli ) 176 and the escape from autophagic recognition ( L. monocytogenes ) 177 . Activation of autophagy through starvation or treatment with rapamycin, a BECN1-derived peptide or other agents restricted bacterial growth and improved cellular or organismal resistance to infection caused by M. tuberculosis (in D. melanogaster and mouse macrophages) 169,178 , S. enterica (in human cancer cell lines) 179 , or pathogenic E. coli (in mice and human cancer cell lines) 180,181 . Moreover, autophagic responses to carbon monoxide protected mice from sepsis induced by cecal ligation and puncture 182 .…”