Nuclear Receptors: Small Molecule Sensors that Coordinate Growth, Metabolism and Reproduction

Abstract

One of the largest groups of metazoan transcription factors (TFs), the Nuclear Receptor superfamily, regulates genes required for virtually all aspects of development, reproduction and metabolism. Together, these master regulators can be thought of as a fundamental operating system for metazoan life. Their most distinguishing feature is a structurally conserved domain that acts as a switch, powered by the presence of small diffusible ligands. This ligand-responsive regulation has allowed the Nuclear Receptors to help their hosts adapt to a wide variety of physiological niches and roles, making them one of the most evolutionarily successful TF families. Originally discovered as receptors for steroid hormones, the Nuclear Receptor field has grown to encompass much more than traditional endocrinology. For example, recent work has highlighted the role of Nuclear Receptors as major regulators of metabolism and biological clocks. By monitoring endogenous metabolites and absorbed xenobiotics, these receptors also coordinate rapid, system-wide responses to changing metabolic and environmental states. While many new Nuclear Receptor ligands have been discovered in the past couple of decades, approximately half of the 48 human receptors are still orphans, with a significantly higher percentage of orphans in other organisms. The discovery of new ligands has led to the elucidation of new regulatory mechanisms, target genes, pathways and functions. This review will highlight both the common as well as newly emerging traits and functions that characterize this particularly unique and important TF family.

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

“…The human genome encodes 48 functional nuclear receptors (10), which sense a multitude of ligands and respond to specific extra-or intracellular stimuli (46,47). Several nuclear receptors scored in an shRNA screen for effects on the yield of HCMV (Fig.…”

Gene-diet interactions and aging in C. elegans

“…Nuclear hormone receptors (NHRs) are ligand-activated transcription factors that sense environmental signals and regulate many fundamental physiological processes, including metabolism, development, and reproduction (Aranda and Pascual, 2001; Sonoda et al, 2008; Pardee et al, 2011). Humans have 48 of these NHRs, while C. elegans have an astounding number of 271 NHRs, many of which are homologs to human NHRs but have yet to be characterized (Pardee et al, 2011; Reece-Hoyes et al, 2005).…”

“…Humans have 48 of these NHRs, while C. elegans have an astounding number of 271 NHRs, many of which are homologs to human NHRs but have yet to be characterized (Pardee et al, 2011; Reece-Hoyes et al, 2005). Perhaps some of these NHRs are involved in sensing certain compounds from the bacteria and activating a downstream physiological response.…”

Spatial and temporal organization of signaling pathways

“…The simplest pathways involve hormone receptors that function as transcription factors; they are activated upon binding of ligands that can enter the cell with no requirement for signal transduction machinery [16,17]. This mechanism provides direct regulation of gene expression but offers little control over signaling range or output diversity.…”