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.