Proteolysis in protein import and export: Signal peptide processing in eu-and prokaryotes

Numerous proteins in pro-and eukaryotes must cross cellular membranes in order to reach their site of function. Many of these proteins carry signal sequences that are removed by specific signal peptidases during, or shortly after, membrane transport. Signal peptidases have been identified in the rough endoplasmic reticulum, the matrix and inner membrane of mitochondria, the stroma and thylakoid membrane of chloroplasts, the bacterial plasma membrane and the thylakoid membrane of cyanobacteria. The composition of these peptidases varies between one and several subunits. No site-specific inhibitors are known for the majority of these enzymes. Accordingly, signal peptidases recognize structural motifs rather than linear amino acid sequences. Such motifs have become evident by employing extensive site-directed mutagenesis to investigate the anatomy of signal sequences. Analysis of the reaction specificities and the primary sequences of several signal peptidases suggests that the enzymes of the endoplasmic reticulum, the inner mitochondrial membrane and the thylakoid membrane of chloroplasts all have evolved from bacterial progenitors.     

Proteolysis in protein import and export: signal peptide processing in eu- and prokaryotes.

Numerous proteins in pro- and eukaryotes must cross cellular membranes in order to reach their site of function. Many of these proteins carry signal sequences that are removed by specific signal peptidases during, or shortly after, membrane transport. Signal peptidases have been identified in the rough endoplasmic reticulum, the matrix and inner membrane of mitochondria, the stroma and thylakoid membrane of chloroplasts, the bacterial plasma membrane and the thylakoid membrane of cyanobacteria. The composition of these peptidases varies between one and several subunits. No site-specific inhibitors are known for the majority of these enzymes. Accordingly, signal peptidases recognize structural motifs rather than linear amino acid sequences. Such motifs have become evident by employing extensive site-directed mutagenesis to investigate the anatomy of signal sequences. Analysis of the reaction specificities and the primary sequences of several signal peptidases suggests that the enzymes of the endoplasmic reticulum, the inner mitochondrial membrane and the thylakoid membrane of chloroplasts all have evolved from bacterial progenitors.     

Interactions between host factors and the skin microbiome

The skin is colonized by an assemblage of microorganisms which, for the most part, peacefully coexist with their hosts. In some cases, these communities also provide vital functions to cutaneous health through the modulation of host factors. Recent studies have illuminated the role of anatomical skin site, gender, age, and the immune system in shaping the cutaneous ecosystem. Alterations to microbial communities have also been associated with, and likely contribute to, a number of cutaneous disorders. This review focuses on the host factors that shape and maintain skin microbial communities, and the reciprocal role of microbes in modulating skin immunity. A greater understanding of these interactions is critical to elucidating the forces that shape cutaneous populations and their contributions to skin homeostasis. This knowledge can also inform the tendency of perturbations to predispose and/or bring about certain skin disorders.     

The molecular basis and clinical aspects of Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is a classic, but not widely known hereditary trait. Its clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of the skin and mucous membranes. In addition, PJS predisposes to cancer . The most common malignancies are small intestinal, colorectal, stomach and pancreatic adenocarcinomas. Other cancer types that probably occur in excess in PJS families include breast and uterine cervical cancer, as well as testicular and ovarian sex cord tumors. The relative risk of cancer may be as high as 18 times that of the general population, and the cancer patients' prognosis is reduced. Recently, the predisposing locus was mapped to 19p13.3 using a novel method. Subsequently, the causative gene was shown to be LKB1 (a.k.a. STK11), a serine/threonine kinase of unknown function. Although preliminary reports seem to suggest a minor role for LKB1 in sporadic tumorigenesis, further investigations are needed. Received 12 October 1998; received after revision 30 November 1998; accepted 30 November 1998     

Amyloid β-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin

The accumulation of aggregates of amyloidogenic peptides is associated with numerous human diseases. One well studied example is the association between deposition of amyloid beta (Abeta) and Alzheimer's disease. Insulin degrading enzyme and neprilysin are involved in the clearance of Abeta, and presequence peptidase is suggested to play a role in the degradation of mitochondrial Abeta. Recent structural analyses reveal that these three peptidases contain a catalytic chamber (crypt) that selectively encapsulates and cleaves amyloidogenic peptides, hence the name cryptidase. The substrate selectivity of these cryptidases is determined by the size and charge distribution of their crypt as well as the conformational flexibility of substrates. The interaction of Abeta with the catalytic core of these cryptidases is controlled by conformational changes that make the catalytic chambers accessible for Abeta binding. These new structural and biochemical insights into cryptidases provide potential therapeutic strategies for the control of Abeta clearance.     

Melatonin,mitochondria, and the skin

The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin–mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.     

Regulation of the H<Superscript>+</Superscript>-ATP synthase by IF1: a role in mitohormesis

The mitochondrial H⁺-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H⁺-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H⁺-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H⁺-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H⁺-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases.     

Functions and pathologies of BiP and its interaction partners

The endoplasmic reticulum (ER) is involved in a variety of essential and interconnected processes in human cells, including protein biogenesis, signal transduction, and calcium homeostasis. The central player in all these processes is the ER-lumenal polypeptide chain binding protein BiP that acts as a molecular chaperone. BiP belongs to the heat shock protein 70 (Hsp70) family and crucially depends on a number of interaction partners, including co-chaperones, nucleotide exchange factors, and signaling molecules. In the course of the last five years, several diseases have been linked to BiP and its interaction partners, such as a group of infectious diseases that are caused by Shigella toxin producing E. coli. Furthermore, the inherited diseases Marinesco-Sj?gren syndrome, autosomal dominant polycystic liver disease, Wolcott-Rallison syndrome, and several cancer types can be considered BiP-related diseases. This review summarizes the physiological and pathophysiological characteristics of BiP and its interaction partners. Received 20 November 2008; received after revision 09 December 2008; accepted 12 December 2008     

The discovery of α-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis

The traditional view of calcium homeostasis is that it is maintained by two essential reactions. First, changes in extracellular Ca²⁺ are sensed in several distinct cell types, stimulating the secretion of parathyroid hormone (PTH), 1,25(OH)₂ D and calcitonin in response to the body’s requirement. Second, these calcitropic hormones then act on the calcium-translocating cells of the kidney, bone, and intestine to restore calcium balance. Recent progress indicates that α-Klotho and fibroblast growth factor (FGF) 23 are key players that integrate the multi-step regulatory system of calcium homeostasis that rapidly adjusts the extracellular calcium concentration and continuously maintains its concentration within a narrow physiological range. α-Klotho and FGF23 are also found to be major players in the regulatory system of phosphate homeostasis. Here, the demonstration of the molecular functions of α-Klotho and FGF23 has recently given new insight into the field of calcium and phosphate homeostasis. Received 3 April 2008; received after revision 23 May 2008; accepted 5 June 2008     

The emerging roles of ribosomal histidyl hydroxylases in cell biology,physiology and disease

Hydroxylation is a novel protein modification catalyzed by a family of oxygenases that depend on fundamental nutrients and metabolites for activity. Protein hydroxylases have been implicated in a variety of key cellular processes that play important roles in both normal homeostasis and pathogenesis. Here, in this review, we summarize the current literature on a highly conserved sub-family of oxygenases that catalyze protein histidyl hydroxylation. We discuss the evidence supporting the biochemical assignment of these emerging enzymes as ribosomal protein hydroxylases, and provide an overview of their role in immunology, bone development, and cancer.     

Human Genome and Diseases:¶The molecular pathogenesis of the Marfan syndrome

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a range of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue collectively termed type-1 fibrillinopathies. Fibrillin-1 is a main component of the 10- to 12-nm extracellular microfibrils that are important for elastogenesis, elasticity, and homeostasis of elastic fibers. Mutations in fibrillin-1 are hypothesized to exert their effects by dominant negative mechanisms, but recent work has also emphasized the potential role of proteases and disturbances in tissue homeostasis in the pathogenesis of the MFS. This article provides an overview of the clinical aspects of the MFS and current thinking on the pathogenesis of this disorder.     

Cutaneous wound healing: recruiting developmental pathways for regeneration

Following a skin injury, the damaged tissue is repaired through the coordinated biological actions that constitute the cutaneous healing response. In mammals, repaired skin is not identical to intact uninjured skin, however, and this disparity may be caused by differences in the mechanisms that regulate postnatal cutaneous wound repair compared to embryonic skin development. Improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for wound healing complications. Here we focus on the roles of several key developmental signaling pathways (Wnt/β-catenin, TGF-β, Hedgehog, Notch) in mammalian cutaneous wound repair, and compare this to their function in skin development. We discuss the varying responses to cutaneous injury across the taxa, ranging from complete regeneration to scar tissue formation. Finally, we outline how research into the role of developmental pathways during skin repair has contributed to current wound therapies, and holds potential for the development of more effective treatments.     

Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. More than one-third of MCC patients will die from this cancer, making it twice as lethal as malignant melanoma. Despite the fact that MCC is still a very rare tumor, its incidence is rapidly increasing; the American Cancer Society estimates for 2008 almost 1 500 new cases in the USA. These clinical observations are especially disturbing as the pathogenesis of MCC is not yet fully understood; however, a number of recent reports contribute to a better understanding of its pathogenesis. Here we describe findings regarding the role of Wnt, MAPK and Akt signaling as well as possible aberrations in the p14ARF/p53/RB tumor suppressor network in MCC. Most important, and possibly with high impact on future therapeutic approaches is the demonstration that a polyomavirus has frequently integrated in the genome of the MCC cells prior to tumor development. Received 12 August 2008; received after revision 06 October 2008; accepted 22 October 2008