The zinc matrix metalloproteinase ZMP-2 increases survival of Caenorhabditis elegans through interference with lipoprotein absorption.

Matrix metalloproteinases are zinc-dependent endopeptidases conserved throughout the animal kingdom which primarily degrade components of the extracellular matrix. In the nematode Caenorhabditis elegans, the zinc matrix metalloproteinase (ZMP-2) was demonstrated to increase resistance versus heat and bacterial pathogens. Here, we show that the survival reducing activities caused by the knockdown of zmp-2 in C. elegans essentially requires the presence of vitellogenin-6, a protein homologous to mammalian apolipoprotein B, and RME-2, a receptor mediating endocytosis of cholesterol particles. Measurements of reactive oxygen species inside and outside C. elegans revealed that knockdown of zmp-2 causes a prooxidative extracellular mileu which is a prerequisite for the reduction of survival. Interestingly, RNAi for the foxo transcription factor daf-16 completely prevented those survival reducing effects of zmp-2 RNAi, and RNAi in mutants of the steroid signalling pathway revealed that DAF-16 acts by inhibition of DAF-9 and DAF-12. In conclusion, our study demonstrates survival reducing activities caused by the functional loss of ZMP-2 in C. elegans. Those effects are mediated by the transport of oxidized cholesterol adducts which then trigger the inhibition of DAF-9 and DAF-12 through the activation of DAF-16.

Vitellogenins increase stress resistance of Caenorhabditis elegans after Photorhabdus luminescens infection depending on the steroid-signaling pathway.

Resistance against environmental stress is a crucial factor in determining the lifespan of organisms. A central role herein has been recently attributed to the transport and storage of lipids with the vitellogenin family emerging as a potential key factor. Here we show that the knockdown of one out of five functional vitellogenin genes, encoding apolipoprotein B homologues, results in a reduced survival of the nematode Caenorhabditis elegans at 37 °C subsequent to infection with the bacterial pathogen Photorhabdus luminescens. An active steroid-signaling pathway, including supply of cholesterol by vitellogenins, steroid ligand formation by the cytochrome P450 dependent DAF-9, and activation of the nuclear hormone receptor DAF-12, in the presence of pathogenic bacteria was associated with reduced nuclear translocation of the forkhead transcription factor DAF-16 and increased antioxidative capacity. Taken together, the study provides functional evidence for a crucial role of vitellogenins and the steroid-signaling pathway in determination of resistance against bacteria.

Phytoestrogens genistein and daidzein affect immunity in the nematode Caenorhabditis elegans via alterations of vitellogenin expression.

SCOPE: Phytoestrogens, such as the soy isoflavones genistein and daidzein, are suggested to beneficially affect lipid metabolism in humans and thereby contribute to healthy ageing. New evidences show that phytoestrogens might slow ageing processes also by affecting immune processes. METHODS AND RESULTS: We tested in the nematode Caenorhabditis elegans the effects of 17ß-estradiol, genistein, and daidzein on resistance versus the nematode pathogen Photorhabdus luminescens with focus on vitellogenins, which are invertebrate estrogen-responsive genes that encode homologues to ApoB100 with impact on immune functions. Here, we show that the estrogen 17ß-estradiol increases the resistance of C. elegans versus P. luminescens by enhancing vitellogenin-expression at the mRNA and protein level. Knockdown of single out of five functional vits by RNA-interference blunted the life-extending effects under heat-stress of 17ß-estradiol, demonstrating a lack of redundancy for the vitellogenins. RNAi for nhr-14, a suggested nuclear hormone receptor for estrogens, displayed no influence on 17ß-estradiol effects. The soy isoflavone genistein reduced vitellogenin-expression and also resistance versus P. luminescens whereas daidzein increased resistance versus the pathogen in a vitellogenin-dependent manner. CONCLUSION: Our studies show that induction of estrogen-responsive vitellogenin(s) by the phytoestrogen daidzein potently increases resistance of C. elegans versus pathogenic bacteria and heat whereas genistein acts in an antiestrogenic manner.

Role of matrix metalloproteinase ZMP-2 in pathogen resistance and development in Caenorhabditis elegans.

The genome of Caenorhabditis elegans includes six homologs of matrix metalloproteinases (MMPs). The C. elegans MMP gene zmp-1 has recently been shown to be involved in anchor cell invasion during post-embryonic vulval development. Here, we identified H19M22.3 (zmp-2) as a pleiotropic MMP gene regulating disease resistance, molting, larval development, and fecundity. Zmp-2(RNAi) nematodes showed significant lifespan reduction during infection with pathogenic Photorhabdus luminescence. Moreover, we observed molting defects indicating a direct or regulative role in extracellular matrix degradation during ecdysis, delayed larval to adult development, and reduced offspring production in hermaphrodite adults. GFP-expressing nematodes revealed predominant expression of zmp-2 in multiple cells during embryogenesis; in hypodermal, muscle, and somatic gonad cells during larval development; and in developing and mature spermathecae in the L4 larval stage and adults. These results give evidence for pleiotropic roles of zmp-2 and provide novel insights into evolutionarily conserved and derived MMP functions in C. elegans.