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.

Keywords: autophagy; host defense; infections; nuclear receptors.

Figure 1

A summarized figure for autophagy genes and different classes of nuclear receptors (NRs). Autophagy processes such as macroautophagy, LC3-associated phagocytosis (LAP), and xenophagy involve different autophagy-related genes (ATGs) or cargo receptors, such as p62, NDP52, and optineurin. The upper panel highlights the different sets of autophagy genes involved in vesicle nucleation, autophagosome formation, and the maturation of autolysosomes. The NR superfamily classes are divided into three or four subclasses according to their structural and functional characteristics and their ligands. NRs are implicated in the regulation of autophagy at transcriptional and post-translational levels. Understanding the mechanisms by which NRs regulate the expression and post-translational modification of ATGs will facilitate the development of novel host-directed antimicrobial agents.

Figure 2

Schematic representation of the signaling pathways of nuclear receptors (NRs) in autophagy-mediated host defense. NRs, including the vitamin D receptor (VDR), estrogen receptor (ER), estrogen-related receptors (ERRs), and peroxisome proliferator-activated receptors (PPARs) have been shown to play critical functions in the regulation of autophagy-mediated host defensive immune responses during infection. These NRs regulate and participate in the autophagic signaling pathways not only at the transcriptional level, but also at the post-transcriptional level. VDR is one of the best characterized NRs related to autophagic function against various infections. It is well-known that VDR signaling increases autophagy activation via the induction of cathelicidin, which is a small cationic antimicrobial peptide. In addition, VDRs functionally link adaptive and innate immune responses by regulating downstream pathways of autophagy. ER activates autophagy by increasing reactive oxygen species (ROS) generation and Akt/ mammalian target of rapamycin (mTOR) signaling. ERRs, which are one of the orphan family members of NR, also regulate a variety of cellular responses, including autophagy. The induction of PGC-1α upregulates the ERRα to promote mitophagy and an antimicrobial effect through sirtuin 1. PPARα activation leads to the expression of transcription factor EB (TFEB) and its nuclear translocation, resulting in the enhancement of lysosomal biogenesis. PPARβ/δ prevents harmful ER stress by increasing autophagy markers Beclin-1 and LC3 II.