**Abstract**

Thanks to the increasing availability of the parasitic Platyhelminthes genomes in recent years, several studies have been directed to the identification of the nuclear receptors set expressed by these organisms. Nevertheless, important gaps in our knowledge remain to be addressed, concerning their mechanism of action, ligands, co-regulator proteins, and DNA binding sequences on target genes. The proposed review chapter will be an account of research into the nuclear receptors field of parasitic Platyhelminthes. Several *in vitro* effects of host steroid hormones on Taenia and Echinococcus species were observed, however, the classical mammalian estrogen, androgen, or progesterone receptors could not be identified in databases. Nonetheless, novel nuclear receptors and related proteins and genes, are being identified and characterized. The elucidation of their target genes as well as ligands in parasitic Platyhelminthes could allow discovery of new and specific pathways differing from those of their hosts. In this sense, these parasitic proteins seem to be good putative targets of new drugs.

**Keywords:** nuclear receptors, parasitic Platyhelminthes, host–parasite relationship

### **1. Introduction**

Since the biochemical identification of the first nuclear receptor (NR) more than 60 years ago [1], the study of these proteins has been increasing. In particular, the cloning of the first NR was a milestone [2], ushering in a new chapter in research into the regulation of cell function and metabolism [3]. NRs are transcription factors that modulate numerous physiological processes such as metabolism, development, reproduction, and inflammation [4–6], through the regulation of target genes transcription by binding to specific DNA response elements [3, 6]. Unlike other transcription factors, the activity of nuclear receptors can be modulated by the binding of specific ligands, these being mainly small lipophilic molecules that easily penetrate biological membranes [7], providing a direct link between the cellular signals and the transcriptional responses of a cell. These lipophilic ligands can be fatty acids, steroids, retinoids, and phospholipids. This protein family also contains "orphan" members for which no ligand has yet been identified [8].

Despite the diversity of functions presented by the different NRs, they share a common modular structure, with various degrees of conservation among their respective domains. A typical nuclear receptor contains an N-terminal domain (NTD or A/B region), a highly conserved DNA binding domain (DBD or C region), a poorly conserved hinge domain (region D), a ligand-binding domain (LBD or E region), and a C-terminal region (F region) [9, 10]. The A/B region is a poorly structured domain that shows a low percentage of conservation at size and sequence level and may not be present in some NRs [6]. This domain is regulated by the interaction with coregulatory proteins and also contains an autonomous transactivation region 1 (AF-1, Activation Factor 1) independent of ligand binding [11]. The DBD is the most conserved region compared to the other domains [12] and it is responsible for the binding of the NR to specific DNA sequences, named response element (RE) [13]. Structural studies have determined that the DBD has two subdomains that each contain four cysteine residues that coordinate a zinc ion to create the typical DNA-binding zinc finger motif [14–16]. The hinge domain is the region with the lowest sequence conservation and it constitutes a flexible linker between the DBD and the LBD [10], giving the connecting domains some independent mobility [17]. The LBD regulates the receptor activity through ligand binding and direct interaction with co-regulatory proteins [18, 19]. This region contains functionally related interaction surfaces: a dimerization surface, which mediates interaction with another LBD [20]; a hydrophobic ligand-binding pocket (LBP) that interacts with lipophilic small molecules [21]; and an activation function surface called AF-2 (Activation Function-2), essential for the ligand-dependent transcription activation [22, 23]. Finally, the F domain is a poorly conserved region, and even many members of the family lack this domain. However, when this domain is present, its deletion or mutation alters transactivation, dimerization, and the receptor response after ligand binding [24].

More than 900 nuclear receptor genes have been identified throughout the animal kingdom [25, 26]. The NRs have a common ancestral origin and a high conservation rate in all animal taxa and therefore are considered strong phylogenetic markers of animal evolution [27]. This protein group shows an interesting complexity probably driven by gene duplication and gene loss [28], for example, 2 members have been identified from sponges, 48 in mammals and up to more than 250 in nematodes [29–32]. Phylogenetic studies demonstrated that NRs emerged long before the divergence of vertebrates and invertebrates, during the earliest metazoan evolution [33]. The nomenclature currently used to name the NRs is based on phylogenetic relationships, generated from conserved DBD sequence alignment and the construction of phylogenetic trees. This classification, which was approved by the Nuclear Receptor Nomenclature Committee in 1999 [34], subdivides the nuclear receptor family into six subfamilies (NR1-NR6). The subfamily NR0 was added later and includes atypical nuclear receptors that contain only DBD (NR0A, identified in arthropods and nematodes) or only LBD (NR0B, present in some vertebrates) [34]. In the last decades, the existence of a new NR subgroup called 2DBD-NR was evidenced in parasitic Platyhelminthes; whose members present two DBDs and one LBD [35, 36]. This new group has not yet been included in the classification system described by the NR Nomenclature Committee [21, 34]. However, recent publications already classify it as a subfamily NR7 [37]. Furthermore, nuclear receptors can be classified according to their mechanism of action into four types (I-IV). This classification groups the NRs according to the signaling mechanisms, taking into account the subcellular site where NR-ligand binding occurs (cytosol or nucleus) and the mode of DNA binding (homodimer, heterodimer, or monomer) [6]. Briefly, type I NRs reside in the cytosol and upon ligand binding are trafficked into the nucleus where they typically bind to palindromic REs in promoters as a homodimer. Type II NRs are localized in the nucleus and generally form

#### *Perspective Chapter: Parasitic Platyhelminthes Nuclear Receptors as Molecular Crossroads DOI: http://dx.doi.org/10.5772/intechopen.102648*

heterodimeric complexes with RXR; in their unliganded state, are inactive and upon ligand binding, they activate by the co-regulators exchange. Type III NRs are similar to Type II, however, these receptors bind to direct repeat REs as homodimers. Type IV NRs have a similar mechanism of action to Type II and III NRs but instead, bind to DNA as a monomer and recognize extended half-sites within RE [6].

Platyhelminthes are a phylum of bilaterian, unsegmented, soft-bodied invertebrates, but also, they are acoelomates and lack specialized circulatory and respiratory organs. These characteristics make these organisms have a flattened shape that allows the exchange of gases and nutrients throughout the body [38]. Platyhelminthes are traditionally divided into four classes: Rhabditophora, Monogenea, Cestoda (tapeworms), and Trematoda (flukes). The class Rhabditophora includes all free-living flatworms, while all members in classes of Monogenea, Trematoda, and Cestoda are parasitic flatworms [39]. The Platyhelminthes or flatworms include more than 20,000 species [40, 41].

Parasitic Platyhelminthes are a large group of parasites that can affect both human and animal health, causing neglected diseases such as Schistosomiasis, Paragonimiasis and Cestodiasis that can be fatal and are difficult to treat. These infections generally lead to pain, physical disabilities, etc., impeding economic development through human disability and billions of dollars of lost production in the livestock industries [42, 43].

In the last decade, the advent of genome projects has allowed the identification of the nuclear receptors expressed in the different parasitic Platyhelminthes [21, 44]. Nevertheless, only a few NRs have been characterized in these organisms and their biological function continues to be unknown. The first parasitic Platyhelminthes NRs were identified in *Schistosoma mansoni* [45–48] and after this, NRs were identified in the genomes of 33 Platyhelminthes species [44, 49]. The number of NRs varies from 15 to 61 in Platyhelminthes, 18–23 NRs are present in Monogenea, 15–20 NRs are present in Cestoda, 21–22 NRs are found in Trematoda, and 27–61 members are identified in Rhabditophora [49]. In this chapter, we performed a systematic review of characteristic and underlying mechanisms of parasitic Platyhelminthes nuclear receptors hoping to provide directions and ideas for future research.
