Jamison D. Feramisco

Cholesterol Addition to ER Membranes Alters Conformation of SCAP, the SREBP Escort Protein that Regulates Cholesterol Metabolism

Sterol accumulation in membranes blocks the exit of SCAP from the ER, preventing SREBP cleavage and reducing cholesterol synthesis. Sterols act through SCAPs sterol-sensing domain by an obscure mechanism. Here, we show that addition of cholesterol to ER membranes in vitro causes a conformational change in SCAP, detected by the unmasking of closely spaced trypsin cleavage sites. Two mutant forms of SCAP (Y298C and D443N) that are refractory to sterol regulation in vivo are also refractory to sterol-induced conformational change in vitro. 25-hydroxycholesterol, a potent regulator of SCAP in vivo, fails to change SCAPs conformation in vitro, suggesting that oxysterols act in intact cells by translocating cholesterol from plasma membrane to ER. These studies demonstrate an in vitro effect of cholesterol on the sterol regulatory machinery.

Membrane Topology of Human Insig-1, a Protein Regulator of Lipid Synthesis

Insig-1 is an intrinsic protein of the endoplasmic reticulum (ER) that regulates the proteolytic processing of membrane-bound sterol regulatory element-binding proteins (SREBPs), transcription factors that activate the synthesis of cholesterol and fatty acids in mammalian cells. When cellular levels of sterols rise, Insig-1 binds to the membranous sterol-sensing domain of SREBP cleavage-activating protein (SCAP), retaining the SCAP/SREBP complex in the ER and preventing it from moving to the Golgi for proteolytic processing. Under conditions of sterol excess, Insig-1 also binds to the ER enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, facilitating its ubiquitination and proteasomal degradation. Here, we use protease protection, glycosylation site mapping, and cysteine derivitization to define the topology of the 277-amino acid human Insig-1. The data indicate that short segments at the N and C termini of Insig-1 face the cytosol. Most of the protein is buried within the membrane, forming six transmembrane segments separated by five short luminal and cytosolic loops that range from ∼5 to 16 amino acids. The membranous nature of Insig-1 is consistent with its sterol-dependent binding to hydrophobic sterol-sensing domains in SCAP and HMG CoA reductase.

Cocaine-associated retiform purpura and neutropenia: Is levamisole the culprit?

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Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step.

Proteasomes mediate the regulated degradation of Insig-1, a membrane protein of the endoplasmic reticulum (ER) that plays a crucial role in lipid metabolism. We showed previously that sterols inhibit this degradation by blocking ubiquitination of Insig-1. Here we show that unsaturated fatty acids stabilize Insig-1 without affecting its ubiquitination. Instead unsaturated fatty acids inhibit extraction of ubiquitinated Insig-1 from membranes, a process known to be mediated by valosin-containing protein and necessary for ER-associated degradation. Valosin-containing protein is recruited to Insig-1 through the action of another protein, Ubxd8. Unsaturated fatty acids block the binding between Ubxd8 and Insig-1, thereby abrogating the membrane extraction of Insig-1. Unsaturated fatty acid-mediated stabilization of Insig-1 enhances the ability of sterols to inhibit proteolytic activation of SREBP-1, which activates transcription of genes involved in fatty acid synthesis. The current study provides a molecular mechanism for regulation of proteasome-mediated ER protein degradation at a postubiquitination step.

Psychoneuroimmunology of Psychological Stress and Atopic Dermatitis: Pathophysiologic and Therapeutic Updates

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.

A gender gap in the dermatology literature? Cross-sectional analysis of manuscript authorship trends in dermatology journals during 3 decades

BACKGROUND Despite a dramatic influx of female dermatologists during the last 30 years, women in academic dermatology departments remain relatively clustered in junior faculty positions. Research in other specialties showing a disparity in the academic productivity of women has led to many hypotheses regarding factors that may place them at a competitive disadvantage. It is unknown, however, whether similar differences in academic productivity might also serve as barriers to advancement in dermatology, or whether any productivity gap actually exists in this specialty that experienced a more substantial entry of women. OBJECTIVE Because publication in peer-reviewed journals is one of the core measures of academic productivity used in the promotion process, we evaluated trends in the prevalence of female authorship in top dermatology journals during the last 3 decades. METHODS We conducted an observational study of trends in the sex distribution of US authors in 3 prestigious general dermatology journals (in 1976, 1986, 1996, and 2006) and 3 subspecialty dermatology journals (in 2006 only). Journals were chosen based on published impact factors and citation half-lives. RESULTS During the last 3 decades, the proportion of women authoring manuscripts in the 3 major general dermatology journals increased from 12% to 48% of US-affiliated first authors (P < .001) and from 6.2% to 31% of US-affiliated senior authors (P < .001). Separate analyses by journal and by article type showed similar increases. The prevalence of female authors in subspecialty journals in 2006 was slightly more variable. LIMITATIONS Although the publications selected for this study capture many of the most respected US journals in dermatology, they may not be representative of all journals in which dermatologists publish. CONCLUSIONS Female dermatologists are authoring publications in growing numbers that match or exceed their prevalence in the academic and overall workforce. This suggests that other factors (differences in productivity outside of the publishing arena, differences in job descriptions or opportunities, differences in career aspirations, a lack of institutional support or flexibility, or gender bias) may be associated with the ongoing reduced advancement of women to senior academic dermatology ranks relative to their male colleagues, and further research is warranted to explore these possibilities.

Receptors, cells and circuits involved in pruritus of systemic disorders

Pruritus is a sensory phenomenon accompanying a broad range of systemic disorders including hematologic and lymphoproliferative disorders, metabolic and endocrine diseases, solid tumours, and infectious diseases. The molecular mechanisms involved in itch sensation remain enigmatic in most of these diseases. However, from studies in patients and animal models a large number of mediators and receptors responsible for scratching behaviour have been identified in recent years. New insights into the interplay between neuronal and non-neuronal cells in the initiation, modulation and sensitization of itch sensation have been acquired. This review highlights the current knowledge of the molecular mechanism involved in pruritus of systemic disorders and summarizes the signalling pathways of biogenic amines, neuropeptides, proteases, eicosanoids, cytokines, opioids, endocannabinoids, neurotrophins, phospholipids and other signalling molecules participating in pruritus.

Innovative Management of Pruritus

Pruritus remains a significant problem facing dermatologists and can be associated with various dermatoses and systemic derangements. At times, one can treat the underlying cutaneous or systemic process to alleviate itch. However, it is frequently challenging to identify the cause of a patients itch and, in this situation, even more difficult to manage the symptom effectively. In this article, the authors discuss the approach to a patient with generalized pruritus without clinically obvious dermatoses. They also addresses mechanisms and management modalities of itch in common systemic diseases, including cholestasis, uremia, and neuropathic dysfunction.

Congenital atrophic dermatofibrosarcoma protuberans in a 7-month-old boy treated with Mohs micrographic surgery.

Abstract:  Dermatofibrosarcoma protuberans is a rare, malignant, slow‐growing, locally invasive tumor of the skin. Although most cases are acquired and diagnosed in adulthood, there have been an increasing number of congenital dermatofibrosarcoma protuberans mimicking benign birthmarks described in the literature. The clinical presentation of this tumor is often one of an indurated exophytic plaque or nodule; however, a rare variant can present as atrophic or sclerotic in nature. We report a case of congenital atrophic dermatofibrosarcoma protuberans of the groin in a 7‐month‐old boy, successfully treated with Mohs micrographic surgery.

Genetics for the Practicing Dermatologist

In the era of robust genome sequencing, a working understanding of genetics has become important for the clinician. For the dermatologist, understanding the flow of genetic information from genotype to phenotype can aid in the delivery of effective patient care. In this article, we will review concepts in genetics and the human genome and how they contribute to clinical dermatology.