Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as sodium, potassium, calcium, and zinc, but their redox-active transition metal counterparts such as copper and iron have been studied primarily as static enzyme cofactors. Here we report that copper is an endogenous regulator of lipolysis, the breakdown of fat, which is an essential process in maintaining the body's weight and energy stores. Utilizing a murine model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we demonstrate that copper regulates lipolysis at the level of the second messenger, cyclic AMP (cAMP), by altering the activity of the cAMP-degrading phosphodiesterase PDE3B. Biochemical studies of the copper-PDE3B interaction establish copper-dependent inhibition of enzyme activity and identify a key conserved cysteine residue within a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype.
HIV-1 is a master at deceiving the immune system, usurping host biosynthetic machinery. Although HIV-1 is coated with host-derived glycoproteins only glycosylation of viral gp120 has been described. Herein we utilize lectin microarray technology to analyze the glycome of intact HIV-1 virions. We show that the glycan coat of human T-cell line-derived HIV-1 matches that of native immunomodulatory microvesicles. The carbohydrate composition of both virus and microvesicles is cell-line dependent, suggesting a mechanism to rapidly camouflage the virus within the host. In addition, binding of both virus and microvesicles to antiviral lectins is enriched over the host cell, raising concern about targeting these glycans for therapeutics. This work also sheds light on the binding of HIV-1 to galectin-1, an important human immune lectin. Overall, our work strongly supports the theory that HIV-1 co-opts the exocytic pathway of microvesicles, potentially explaining why eliciting a protective antiviral immune response is difficult.
Introduction The metastatic progression of cancer is a direct result of the disregulation of numerous cellular signaling pathways, including those associated with adhesion, migration, and invasion. Members of the Rac family of small GTPases are known to act as regulators of actin cytoskeletal structures and strongly influence the cellular processes of integrin-mediated adhesion and migration. Even though hyperactivated Rac proteins have been shown to influence metastatic processes, these proteins have never been directly linked to metastatic progression.
Carbohydrates encode biological information necessary for cellular function. The structural diversity and complexity of these sugar residues have necessitated the creation of novel methodologies for their study. This review highlights recent technological advancements that are starting to unravel the intricate web of carbohydrate biology. New methods for the analysis of both glycoconjugates and glycan structures are discussed. With the use of these innovative tools, the field of glycobiology is poised to take center-stage in the post-genomic era of modern biology and medicine. Glycomics or the systems-level study of carbohydrates (glycans) has emerged as an important area of research in the post-genomic era. Although proteins are tagged with a variety of post-translational modifications including phosphorylation, acetylation, and methylation, glycosylation is the most prevalent modification, occurring on at least 50% of all proteins (1). The vast majority of glycoproteins and glycolipids are found at the cell membrane creating a carbohydrate-coated surface which communicates with the extracellular world. Interactions with cell surface oligosaccharides play a critical role in numerous biological events including differentiation, cellular adhesion, immune responses, and host-pathogen interactions (2-7). For example, the expression of an α-2,6-sialyltransferase (ST6GALNAC5) has been shown to mediate metastasis of breast cancer cells to the brain by enhancing adhesion of tumor cells to brain tissue (8). Although there is increasing evidence for critical biological roles of carbohydrates, the challenges posed by the diversity of glycans have slowed progress in understanding this class of biopolymers. This review delineates the challenge of glycomics and how it is being met by the advent of new technologies to analyze both structural and functional aspects of carbohydrates.
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