Metabolic Reconfiguration in C. elegans Suggests a Pathway for Widespread Sterol Auxotrophy in the Animal Kingdom

Abstract

Cholesterol is one of the hallmarks of animals. In vertebrates, the cholesterol synthesis pathway (CSP) is the primary source of cholesterol that has numerous structural and regulative roles [1]. Nevertheless, the few invertebrates tested for cholesterol synthesis show complete sterol auxotrophy [2-6], raising questions about how animals thrive without cholesterol synthesis and about the prevalence of sterol auxotrophy in animals. In the nematode Caenorhabditis elegans (C. elegans), sterols are the precursors of the steroid hormone dafachronic acid that coordinates development to adulthood [7,8]; thus, sterol-deprived C. elegans arrest at the diapause ''dauer'' larval stage [9]. Using this system, we have identified a pathway that converts plant and fungal sterols into cholesterol through the activity of enzymes with sequence similarity to specific human CSP enzymes. Based on this finding, we propose that two critical steps shaped the evolution of animal sterol auxotrophy: (1) the loss of the orthologs of the first three enzymes of the CSP and (2) the co-opting of other downstream enzymes of the CSP for the utilization of dietary sterols. Using this mechanistic signature, we studied the evolution of cholesterol auxotrophy across the animal kingdom. Complete sets of CSP enzymes in basal animals suggest that the loss of cholesterol synthesis occurred during animal evolution. A sterol auxothropy signature in the genomes of many invertebrates, including nematodes and most arthropods, suggests widespread cholesterol auxotrophy in animals. Thus, we propose that this co-opted pathway supports widespread cholesterol auxotrophy by interkingdom interactions between cholesterol-auxotrophic animals and sterol-producing fungi and plants.

Phytophthora capsici sterol reductase PcDHCR7 has a role in mycelium development and pathogenicity

“…Despite the vital role of sterols some organisms are sterol auxothrophs; they cannot synthesize sterols and have to recruit exogenous sterols via ingestion or absorption. Sterol auxotrophs include nematodes, most arthropods, many ciliates, and some genera of oomycetes (Shamsuzzama et al, 2020;Tomazic et al, 2014;Gaulin et al, 2010). Oomycetes are a diverse group of eukaryotic microorganisms in the Stramenopile lineage that comprises quite a number of devastating filamentous plant and animal pathogens (Govers and Gijzen, 2006;Kamoun et al, 2015).…”

The mysterious route of sterols in oomycetes

“…Despite the essential role of sterols in cell functioning in eukaryotes, several organisms, including nematodes, insects, and plasmodia, are not able to synthesize sterols themselves. To sustain normal development, these sterol auxotrophs may have to acquire exogenous sterols from their food or environment [ 5 , 6 ].…”

Molecular insights into symbiosis—mapping sterols in a marine flatworm-algae-system using high spatial resolution MALDI-2-MS imaging with ion mobility separation

“…This could be due to relatively fast absorption of algae-produced sterols and their distribution within the organism, as well as a possible slow turnover of sterols in host tissues such that concentrations in host membranes are sufficiently high as to appear indistinguishable from the algal sources. Finally, it is possible that some sterols could be modified or converted by host enzymes [55], which warrants future investigation.…”