The sterol regulatory element binding protein (SREBP) family of transcription activators are critical regulators of cholesterol and fatty acid homeostasis. We previously demonstrated that human SREBPs bind the CREB-binding protein (CBP)/p300 acetyltransferase KIX domain and recruit activator-recruited co-factor (ARC)/Mediator co-activator complexes through unknown mechanisms. Here we show that SREBPs use the evolutionarily conserved ARC105 (also called MED15) subunit to activate target genes. Structural analysis of the SREBP-binding domain in ARC105 by NMR revealed a three-helix bundle with marked similarity to the CBP/p300 KIX domain. In contrast to SREBPs, the CREB and c-Myb activators do not bind the ARC105 KIX domain, although they interact with the CBP KIX domain, revealing a surprising specificity among structurally related activator-binding domains. The Caenorhabditis elegans SREBP homologue SBP-1 promotes fatty acid homeostasis by regulating the expression of lipogenic enzymes. We found that, like SBP-1, the C. elegans ARC105 homologue MDT-15 is required for fatty acid homeostasis, and show that both SBP-1 and MDT-15 control transcription of genes governing desaturation of stearic acid to oleic acid. Notably, dietary addition of oleic acid significantly rescued various defects of nematodes targeted with RNA interference against sbp-1 and mdt-15, including impaired intestinal fat storage, infertility, decreased size and slow locomotion, suggesting that regulation of oleic acid levels represents a physiologically critical function of SBP-1 and MDT-15. Taken together, our findings demonstrate that ARC105 is a key effector of SREBP-dependent gene regulation and control of lipid homeostasis in metazoans.

Summary Sterol Regulatory Element-Binding Proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids, and therefore are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can result in excess stored fat and contribute to obesity, fatty liver disease and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls production of the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a mechanism where maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.

How does the nervous system encode environmental stimuli as sensory experiences? Both the type (visual, olfactory, gustatory, mechanical or auditory) and the quality of a stimulus (spatial position, intensity or frequency) are represented as a neural code. Here we undertake a genetic analysis of sensory modality coding in Caenorhabditis elegans. The ASH sensory neurons respond to two distinct sensory stimuli (nose touch and osmotic stimuli). A mutation in the glr-1 (glutamate receptor) gene eliminates the response to nose touch but not to osmotic repellents. The predicted GLR-1 protein is roughly 40% identical to mammalian AMPA-class glutamate receptor (GluR) subunits. Analysis of glr-1 expression and genetic mosaics indicates that GLR-1 receptors act in synaptic targets of the ASH neurons. We propose that discrimination between the ASH sensory modalities arises from differential release of ASH neurotransmitters in response to different stimuli.

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Neuropeptides play critical roles in synaptic signaling in all nervous systems. Unlike classical neurotransmitters, peptidergic neurotransmitters are encoded as preproproteins that are posttranslationally processed to yield bioactive neuropeptides. To identify novel peptidergic neurotransmitters, the Caenorhabditis elegans genome was searched for predicted proteins with the structural hallmarks of neuropeptide preproproteins. Thirty-two C. elegans neuropeptide-like protein (nlp) genes were identified. The nlp genes define at least 11 families of putative neuropeptides with unique motifs; similar expressed sequence tags were identified in other invertebrate species for all 11 families. Six of these families are defined by putative bioactive motifs (FAFA, GGxYamide, MRxamide, LQFamide, LxDxamide, and GGARAF); the remaining five families are related to allatostatin, myomodulin, buccalin͞drosul-fakinin, orcokinin, and APGWamide neuropeptides (MGL͞Famide, FRPamide, MSFamide, GFxGF, and YGGWamide families, respectively). Most C. elegans nlp gene expression is in neurons. The C. elegans nlp genes and similar genes encoding putative neuropeptides in other species are likely to play diverse roles in nervous system function. C hemical signaling via neurotransmitters is critical for synaptic transmission of information between neurons. Neuropeptides are the most varied and numerous type of neurotransmitters. Invertebrate neuropeptides are thought primarily to modulate synaptic function of classical small-molecule neurotransmitters by means of seven transmembrane domain receptors. However, the recent identification of a FMRFamide-gated sodium channel from Helix lucorum suggests that they may also act as fast transmitters (1). In mammals, neuropeptides and their receptors are implicated in behaviors including feeding and sleep (2-5). Despite their clear roles in synaptic signaling and behavior, neuropeptide functions are still not understood.Biochemical isolation of neuropeptides has been relatively successful in several invertebrate systems, including Lymnaea stagnalis, Drosophila melanogaster, and Aplysia californica (6-8), and has led to the identification of several invertebrate neuropeptide families. In the nematode Caenorhabditis elegans, 23 FMRFamide-related proteins (FaRP) neuropeptide genes, designated flp-1 to flp-23 (FMRFamide-like proteins), have been identified (9). Only flp-1 has been characterized at the functional level. Animals lacking flp-1 have abnormal behavior, including uncoordinated movement and hyperactivity (10). The only other C. elegans non-flp neuropeptide genes that have been identified are the 37 insulin-like genes (11, 12).Dense-core synaptic vesicles are prevalent in presynaptic terminals of C. elegans neurons that are neither FaRP immunoreactive nor catecholaminergic (13), suggesting that nonFaRP neuropeptides are present. Additionally, about 130 genes encoding putative neuropeptide receptors were identified in the C. elegans genome (14). This large number of receptors is much higher than the...