Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
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.
Hannich
J Thomas
JT
Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
Entchev
Eugeni V
EV
Mende
Fanny
F
Boytchev
Hristio
H
Martin
René
R
Zagoriy
Vyacheslav
V
Theumer
Gabriele
G
Riezman
Isabelle
I
Riezman
Howard
H
Knölker
Hans-Joachim
HJ
Kurzchalia
Teymuras V
TV
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002782:Cholestenes / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007814:Larva / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010675:Pheromones / Q000494:pharmacology; D011496:Protein Methyltransferases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects
D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; C410905:DAF-12 protein, C elegans; D010675:Pheromones; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; C533800:dafachronic acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C486228:DAF-9 protein, C elegans; D008780:Methyltransferases; D011496:Protein Methyltransferases; C541929:STRM-1 protein, C elegans