Introduction
Corals are colonies of marine invertebrates (cnidarians) that depend on a symbiotic relationship with algae in the family Symbiodiniaceae (LaJeunesse et al., 2018). The algae harvest light and synthesize nutrients in exchange for shelter and nitrogen sources (Putnam et al., 2017). Coral reefs cover only 0.1% of the ocean floor, but are home to the largest density of animals on earth, rivaling rain forest habitats in species diversity (Hoegh-Guldberg et al., 2017). The symbiosis, which was originally thought to be restricted to algae, is now known to extend to a much more complex community than anticipated with thousands of bacteria, bacteriophages, viruses and fungi, in addition to algae. The entirety of the organism community in a coral is referred to as a holobiont. Individual cnidarian host animals are called polyps.
Symbiosis characterizes the healthy host-microbial coral community. It is essentially unknown what molecules are responsible for the complex communication mechanisms that allow symbiosis to occur (Gates et al., 1995). This is a particularly severe gap in our knowledge, since it is at the heart of the worldwide phenomenon of coral reef bleaching, in which the algae are leaving the cnidarian host as a result of temperature stress, including that brought about by global warming. A recent study assessed 100 worldwide locations and found that the annual risk of coral bleaching has increased from an expected 8% of locations in the early 1980s to 31% in 2016 (Gates et al., 1995; Hughes et al., 2018). Human impacts on coral reef ecosystems threaten fishing and tourism industries that are valued at hundreds of billion of dollars annually (Putnam et al., 2017). Finding potential solutions to assist the corals in the survival of human impact is an urgent task.
The symbiotic algae are believed to provide as much as 90% of the energy the corals consume by light harvesting and photosynthesis. Thus, it is likely that corals can measure and regulate nutrient balance. Support for this hypothesis comes from transcriptomic studies (Yuyama et al., 2018). A comparison between the expression of insulin signaling related genes in the presence and absence of the symbiotic algae strongly suggests that insulin signaling is induced at the transcriptomic level in response to population of the corals by the algae. A likely interpretation of this finding is that the coral needs to respond to the sugars that are produced by the algae and perhaps too much sugar could have detrimental effects on corals, similar to the diabetic response through aberrant insulin signaling in humans. It is also possible that the mechanism for bleaching (loss of symbiotic algae from the holobiont) involves an imbalance in nutrient regulation and possible involvement of the insulin signaling pathway. Could corals have diabetes?
The first step in addressing such questions is to establish the extent to which insulin signaling in corals is analogous to human insulin signaling. The animal host in corals are cnidarians which have evolved before the split into deuterostomia such as humans and protostomia like the model organisms Caenorhabditis elegans and Drosophila melanogaster 700 Million years ago. During this time, mutations accumulated, so we expect many homologues between humans and corals to be in the gray zone of 20-30% sequence identity, usually referred to as remote homology. Therefore, identifying similarity between human and coral genes requires remote homology detection and analysis. The coral we have chosen for this project is Pocillopora damicornis (pdam), a stony coral that makes its own calcium carbonate skeleton and houses colonies of individual animals, the polyps, just barely visible by eye. First, we identified the most likely homologue of human insulin and insulin receptor (IR) as well as downstream pdam homologues in the insulin related signaling pathways involving over 100 proteins using a Hidden Markov Modeling approach suitable for the large divergence between sequences, hhblits (Remmert et al., 2011). Next, we investigated in detail through computational structural modeling the conservation of amino acids crucial for function, especially ligand binding. Finally, we compared the conservation of the interface of the IR with its natural ligand insulin to those of small molecule pharmacological agents developed originally for targeting the human IR. This included small molecule agonists and sensitizers as well as inhibitors, which have been studied in humans for their potential clinical applications in treatment of diabetes and cancer, respectively. Our study opens the door to a new field in coral biology, that of coral pharmacology.