Methylation of the Sterol Nucleus by STRM-1 Regulates Dauer Larva Formation in Caenorhabditis elegans

Abstract

In response to pheromone(s), Caenorhabditis elegans interrupts its reproductive life cycle and enters diapause as a stress-resistant dauer larva. This decision is governed by a complex system of neuronal and hormonal regulation. All the signals converge onto the nuclear hormone receptor DAF-12. A sterol-derived hormone, dafachronic acid (DA), supports reproductive development by binding to DAF-12 and inhibiting its dauer-promoting activity. Here, we identify a methyltransferase, STRM-1, that modulates DA levels and thus dauer formation. By modifying the substrates that are used for the synthesis of DA, STRM-1 can reduce the amount of hormone produced. Loss of STRM-1 function leads to elevated levels of DA and inefficient dauer formation. Sterol methylation was not previously recognized as a mechanism for regulating hormone activity. Moreover, the C-4 sterol nucleus methylation catalyzed by STRM-1 is unique to nematodes and thus could be a target for therapeutic strategies against parasitic nematode infections.

Integration of carbohydrate metabolism and redox state controls dauer larva formation in Caenorhabditis elegans

“…As they are localized to the same cells, regulation via depletion of either substrate or cofactor can be executed within the cell. This is reminiscent of another dauer regulator, STRM-1, which is localized to the hypodermis where methylation of cholesterol occurs 15 . Finally, DAF-16 and DAF-12 inhibited NADPH formation at the transcriptional level by (a) enhancing trehalose biosynthetic enzymes and (b) downregulating IDH-1.…”

“…All single mutants were outcrossed at least three times. Compound mutant and transgenic strains were produced during this study or past studies as published 15,16 or described below. daf-9(dh6);dhEx24 and daf-9(dh6);daf-12(rh61rh411) were provided by the group of Dr A. Antebi.…”

“…Strong expression occurred predominantly in the hypodermis (Fig. 2e), a tissue in which DAF-9 and STRM-1 are also expressed 14,15,22 . Some expression was observed in a number of head neurons and in the isthmus of the pharynx, and no expression was seen in the intestinal cells (Fig.…”

“…Conversely, we recently showed that DAF-12 regulates dauer formation via a negative feedback loop by decreasing one of the substrates used for DA synthesis, cholesterol. DAF-12 activates STRM-1, a methylase that renders cholesterol unsuitable for DA synthesis 15 . Thus, DAF-16 and/or DAF-12 could act in a similar way to decrease the level of NADPH, the other substrate for DA synthesis, for example, by activation of TPS-1/2 or downregulation of the activity of PPP and/or IDH-1.…”

“…One of the mechanisms regulating biosynthesis of DA may be the modulation of the concentration of substrates required for its synthesis. Recently, we showed that methylation of cholesterol in the fourth position by the sterol methylase STRM-1 renders cholesterol unsuitable for DA synthesis 15 . Another cofactor for DA production is cytosolic NADPH, which is used by DAF-9 as an electron donor 13 .…”