Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

Abstract

Autophagy is an intracellular process that targets intracellular pathogens for lysosomal degradation. Autophagy is tightly controlled at transcriptional and post-translational levels. Nuclear receptors (NRs) are a family of transcriptional factors that regulate the expression of gene sets involved in, for example, metabolic and immune homeostasis. Several NRs show promise as host-directed anti-infectives through the modulation of autophagy activities by their natural ligands or small molecules (agonists/antagonists). Here, we review the roles and mechanisms of NRs (vitamin D receptors, estrogen receptors, estrogen-related receptors, and peroxisome proliferator-activated receptors) in linking immunity and autophagy during infection. We also discuss the potential of emerging NRs (REV-ERBs, retinoic acid receptors, retinoic acid-related orphan receptors, liver X receptors, farnesoid X receptors, and thyroid hormone receptors) as candidate antimicrobials. The identification of novel roles and mechanisms for NRs will enable the development of autophagy-adjunctive therapeutics for emerging and re-emerging infectious diseases.

Epigenetic Regulation of Autophagy in Bone Metabolism

“…Epigenetic mechanisms are crucial in regulating autophagy processes, influencing its transcriptional and post-translational regulation. 195 , 196 These epigenetic mechanisms can be further influenced by external stimuli, alterations in phenotypic states, or pathological environmental conditions. 197 Epigenetic modifications and autophagy interact in bone metabolism, regulating gene expression, cellular clearance, and stress responses, crucial for maintaining bone tissue homeostasis and function.…”

Archaic connectivity between the sulfated heparan sulfate and the herpesviruses – An evolutionary potential for cross-species interactions

“…There are also indications that retinol supplementation shows promise as a preventative and therapeutic treatment for infection [67] , [68] . To our knowledge, it is unknown whether the presence of HSV interferes with typical retinoid receptor expression or the relative presence of their ligands; however, it is hypothesized that if HSV causes the up- or downregulation of retinoid receptors as other pathogens do [69] , it may have serious consequences on development. Future research may be necessary to test the relevance of such mechanisms to HSV teratology.…”

Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors

“…Autophagy is an evolutionarily conserved degradation process delivering intracellular cargo molecules to lysosomes. These cargos include glycogen, lipid droplets, aggregated proteins, membrane-enclosed organelles, and infected parasites [ 1 , 21 , 22 ]. Although most cells and tissues maintain a constant level of basal autophagy, numerous stimuli tremendously elevate autophagy activity.…”