Adiponectin is a plasma protein expressed exclusively in adipose tissue. Adiponectin levels are linked to insulin sensitivity, but a direct effect of chronically elevated adiponectin on improved insulin sensitivity has not yet been demonstrated. We identified a dominant mutation in the collagenous domain of adiponectin that elevated circulating adiponectin values in mice by 3-fold. Adiponectinemia raised lipid clearance and lipoprotein lipase activity, and suppressed insulin-mediated endogenous glucose production. The induction of adiponectin during puberty and the sexual dimorphism in adult adiponectin values were preserved in these transgenic animals. As a result of elevated adiponectin, serum PRL values and brown adipose mass both increased. The effects on carbohydrate and lipid metabolism were associated with elevated phosphorylation of 5'-AMP-activated protein kinase in liver and elevated expression of peroxisomal proliferator-activated receptor gamma2, caveolin-1, and mitochondrial markers in white adipose tissue. These studies strongly suggest that increasing endogenous adiponectin levels has direct effects on insulin sensitivity and may induce similar physiological responses as prolonged treatment with peroxisomal proliferator-activated receptor gamma agonists.

Retroviral integration is catalyzed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome1,2. How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy (EM) reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location (SHL) ±3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration.

Analysis of the lipid composition of influenza virus–infected cells provides support for the membrane raft-based biogenesis model.

Signal peptides (SP) are key determinants for targeting glycoproteins to the secretory pathway. Here we describe the involvement in particle maturation as an additional function of a viral glycoprotein SP. The SP of foamy virus (FV) envelope glycoprotein is predicted to be unusually long. Using an SP-specific antiserum, we demonstrate that its proteolytic removal occurs posttranslationally by a cellular protease and that the major N-terminal cleavage product, gp18, is found in purified viral particles. Analysis of mutants in proposed signal peptidase cleavage positions and N-glycosylation sites revealed an SP about 148 amino acids (aa) in length. FV particle release from infected cells requires the presence of cognate envelope protein and cleavage of its SP sequence. An N-terminal 15-aa SP domain with two conserved tryptophan residues was found to be essential for the egress of FV particles. While the SP N terminus was found to mediate the specificity of FV Env to interact with FV capsids, it was dispensable for Env targeting to the secretory pathway and FV envelopemediated infectivity of murine leukemia virus pseudotypes.Signal peptides (SP) are key determinants for targeting and membrane insertion of secretory and membrane proteins (reviewed in reference 25). They can be removed co-or posttranslationally by the cellular membrane-bound signal peptidase or may, if not cleaved, serve as membrane anchors for proteins with distinct membrane orientations. In general, SP are composed of three domains, of which a central 6-to 15-amino-acid (aa)-long hydrophobic domain (h-domain) is the most essential. An N-terminal polar domain (n-domain) usually of net positive charge shows high variability in overall length, ranging from 15 to more than 50 aa. The composition and structure of the n-domain influences protein orientation in the membrane. The polar C-terminal domain (c-domain) often contains helixbreaking as well as small uncharged residues in positions -3 and -1 which determine the site of SP cleavage. In most cases, SP cleavage is thought to occur cotranslationally; however, for some proteins, e.g., the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp160, SP cleavage occurs inefficiently and very late after translocation (21). A basic amino acid stretch in the n-domain of gp160 is responsible for this phenomenon and believed to influence folding and exit of HIV-1 Env from the endoplasmic reticulum (ER) (21). Recent studies revealed that SP bear specific information accounting for distinct functions in targeting and membrane insertion or even for defined metabolic pathways after their cleavage from the parent protein (reviewed in reference 25). The HIV-1 SP Env , for example, is further processed by the signal peptidase, leading to the release of an SP fragment into the cytosol, where it binds to calmodulin (26). The function of this process in viral replication is not known.Foamy viruses (FV), as studied with the prototype member human foamy virus (HFV), follow a replication cycle which is charact...

SUMMARY Aicardi-Goutières syndrome (AGS), a hereditary autoimmune disease, clinically and biochemically overlaps with systemic lupus erythematosus (SLE) and, like SLE, is characterized by spontaneous type I interferon (IFN) production. The finding that defects of intracellular nucleases cause AGS led to the concept that intracellular accumulation of nucleic acids triggers inappropriate production of type I IFN and autoimmunity. AGS can also be caused by defects of SAMHD1, a 3′ exonuclease and deoxy-nucleotide (dNTP) triphosphohydrolase. Human SAMHD1 is an HIV-1 restriction factor that hydrolyzes dNTPs and decreases their concentration below the levels required for retroviral reverse transcription. We show in gene-targeted mice that also mouse SAMHD1 reduces cellular dNTP concentrations and restricts retroviral replication in lymphocytes, macrophages, and dendritic cells. Importantly, the absence of SAMHD1 triggered IFN-β-dependent transcriptional upregulation of type I IFN-inducible genes in various cell types indicative of spontaneous IFN production. SAMHD1-deficient mice may be instrumental for elucidating the mechanisms that trigger pathogenic type I IFN responses in AGS and SLE.