NR1D1 amelioratesMycobacterium tuberculosisclearance through regulation of autophagy

Abstract

Abbreviations: 3-MA, 3-methyladenine; AO, acridine orange; ARNTL/BMAL1, aryl hydrocarbon receptor nuclear translocator-like; AVOs, acidic vesicular organelles; CFU, colony forming unit; LAMP1, lysosomal-associated membrane protein 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MDC, monodansylcadaverine; PFA, paraformaldehyde; PIK3C3/VPS34, phosphatidylinositol 3-kinase, catalytic subunit type 3; PMA, phorbol 12-myristate 13-acetate; SD, standard deviation; TFEB, transcription factor EB; ULK1, unc-51 like autophagy activating kinase 1; V-ATPase, vacuolar-type H C ATPase; VPS11, vacuolar protein sorting 11 homolog (S. cerevisiae).NR1D1 (nuclear receptor subfamily 1, group D, member 1), an adopted orphan nuclear receptor, is widely known to orchestrate the expression of genes involved in various biological processes such as adipogenesis, skeletal muscle differentiation, and lipid and glucose metabolism. Emerging evidence suggests that various members of the nuclear receptor superfamily perform a decisive role in the modulation of autophagy. Recently, NR1D1 has been implicated in augmenting the antimycobacterial properties of macrophages and providing protection against Mycobacterium tuberculosis infection by downregulating the expression of the IL10 gene in human macrophages. This antiinfective property of NR1D1 suggests the need for an improved understanding of its role in other host-associated antimycobacterial pathways. The results presented here demonstrate that in human macrophages either ectopic expression of NR1D1 or treatment with its agonist, GSK4112, enhanced the number of acidic vacuoles as well as the level of MAP1LC3-II, a signature molecule for determination of autophagy progression, in a concentration-and timedependent manner. Conversely, a decrease in NR1D1 in knockdown cells resulted in the reduced expression of lysosomal-associated membrane protein 1, LAMP1, commensurate with a decrease in the level of transcription factor EB, TFEB. This is indicative of that NR1D1 may have a regulatory role in lysosome biogenesis. NR1D1 being a repressor, its positive regulation on LAMP1 and TFEB is suggestive of an indirect byzantine mechanism of action. Its role in the modulation of autophagy and lysosome biogenesis together with its ability to repress IL10 gene expression supports the theory that NR1D1 has a pivotal antimycobacterial function in human macrophages.

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

“…Because TFEB is a master regulator of, and essential transcription factor for, lysosomal biogenesis and control of xenophagy during M. tuberculosis infection [20,52], the regulatory mechanisms of TFEB activation are critical for the antimycobacterial response. Nuclear receptor subfamily 1, group D, member 1, an adopted orphan nuclear receptor, plays an important role in the regulation of TFEB transcription [53]. Although we did not examine the effect of TFEB on the inflammatory response during Mabc infection, we reported previously that TFEB silencing enhanced the inflammatory response of macrophages infected with M. tuberculosis [20].…”

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…Advances have recently been made toward our understanding of the transcriptional regulation of Atgs that function in autophagic processes and numerous physiological responses, including innate host defense against mycobacterial infection. As an example, recent studies have shown that activation of NR1D1 (an adopted orphan nuclear receptor subfamily 1, group D, member 1) enhances autophagy and the expression of LAMP1 and TFEB, to promote antimycobacterial effects in human macrophages (37). We reported previously that the AMPK-PGC1a pathway is essential for transcriptional activation of Atgs, including Atg5, Becn1, and Atg7, in macrophages via C/EBP-b signaling activation (18).…”

Autophagy: A new strategy for host-directed therapy of tuberculosis

“…Several nuclear receptor agonists have promising effects on host autophagy and antimicrobial defense in mycobacterial infection. Chandra et al [60] showed that nuclear receptor subfamily 1, group D, member 1 (NRD1), an adopted orphan nuclear receptor, is involved in the enhancement of antimycobacterial effects and autophagy in human macrophages. NR1D1 contributes to the activation of autophagy and lysosomal biogenesis via an increase in MAP1LC3-II and the lysosomal protein LAMP1.…”