The lipophosphoglycan of Leishmania

The major cell surface glycoconjugate of leishmanial parasites is lipophosphoglycan (LPG). Its relative abundance, unique structure, and cellular location suggest one or more important roles in interactions between parasites and host cells. In this article, Sam Turco examines current information about this novel glycoconjugate and its significance.     

Rush to the fire: FGF21 extinguishes metabolic stress,metaflammation and tissue damage

FGF21 is a master regulator of homeostasis of local and systemic lipid, glucose and energy metabolism. Since its discovery a decade ago, significant progress has been made in understanding the basic molecular, cellular and physiological mechanisms underlying its metabolic roles, and characterizing its beneficial pharmacological activities and possible pathological roles in obesity, diabetes, dyslipidemia, fatty liver disease and their collateral complications and tissue damage. Under basal or normal conditions, FGF21 appears to play a dispensable role in metabolism. However, in response to a variety of cellular and metabolic stress, FGF21 is significantly upregulated to serve as a potent catabolic factor leading to the clearance of excessive lipids and glucose, and therefore, antagonizes metabolic and energy imbalance in a negative fashion. Furthermore, FGF21 treatment ameliorates tissue damage resulted from the harmful effects of metabolic abnormalities, which often ensue an oxidative, pro-inflammatory, inflammatory and/or immune stress state, the so-called metaflammation. Most notably, studies focusing on the liver, pancreas, cardio-vasculature and kidney have revealed its significant protective effects against the structural and functional damages induced by the obese, diabetic or other abnormal metabolic conditions. In this review, we will summarize the current progress on the roles of FGF21 against metaflammation and metabolic tissue damage.     

Dynein: An ancient motor protein involved in multiple modes of transport

Cytoplasmic dynein has long been thought to be responsible for retrograde axonal transport. As the number of cellular roles for this multifunctional protein has expanded, the complexity of its contribution to axonal transport has increased. In this article the increasing evidence for a role for cytoplasmic dynein in anterograde as well as retrograde transport is discussed. The current status of the complex dynein cargo-binding mechanism is evaluated. Finally, recent genetic evidence supporting a role in axonal transport and revealing a role in neurodegenerative conditions is reviewed.     

New mechanisms and functions of actin nucleation

In cells the de novo nucleation of actin filaments from monomers requires actin-nucleating proteins. These fall into three main families--the Arp2/3 complex and its nucleation promoting factors (NPFs), formins, and tandem-monomer-binding nucleators. In this review, we highlight recent advances in understanding the molecular mechanism of actin nucleation by both well-characterized and newly identified nucleators, and explore current insights into their cellular functions in membrane trafficking, cell migration and division. The mechanisms and functions of actin nucleators are proving to be more complex than previously considered, with extensive cooperation and overlap in their cellular roles.     

Neutral sphingomyelinases and nSMase2: Bridging the gaps

There is strong evidence indicating a role for ceramide as a second messenger in processes such as apoptosis, cell growth and differentiation, and cellular responses to stress. Ceramide formation from the hydrolysis of sphingomyelin is considered to be a major pathway of stress-induced ceramide production with magnesium-dependent neutral sphingomyelinase (N-SMase) identified as a prime candidate in this pathway. The recent cloning of a mammalian N-SMase-nSMase2- and generation of nSMase2 knockout/mutant mice have now provided vital tools with which to further study the regulation and roles of this enzyme in both a physiological and pathological context. In the present review, we summarize current knowledge on N-SMase relating this to what is known about nSMase2. We also discuss the future areas of nSMase2 research important for molecular understanding of this enzyme and its physiological roles.     

SUMOylation and de-SUMOylation in response to DNA damage

To maintain genomic integrity, a cell must utilize multiple mechanisms to protect its DNA from the damage generated by environmental agents or DNA metabolism. SUMO (small ubiquitin-like modifier) can regulate protein stability, protein cellular location, and protein-protein interactions. In this review, we summarize the current understanding of the roles of SUMOylation and de-SUMOylation in DNA damage response (DDR) and DNA repair with a specific focus on the role of RPA SUMOylation in homologous recombination (HR).     

Neutral sphingomyelinases and nSMase2: bridging the gaps

There is strong evidence indicating a role for ceramide as a second messenger in processes such as apoptosis, cell growth and differentiation, and cellular responses to stress. Ceramide formation from the hydrolysis of sphingomyelin is considered to be a major pathway of stress-induced ceramide production with magnesium-dependent neutral sphingomyelinase (N-SMase) identified as a prime candidate in this pathway. The recent cloning of a mammalian N-SMase-nSMase2- and generation of nSMase2 knockout/mutant mice have now provided vital tools with which to further study the regulation and roles of this enzyme in both a physiological and pathological context. In the present review, we summarize current knowledge on N-SMase relating this to what is known about nSMase2. We also discuss the future areas of nSMase2 research important for molecular understanding of this enzyme and its physiological roles.     

Differentiating connexin hemichannels and pannexin channels in cellular ATP release

Adenosine triphosphate (ATP) plays a fundamental role in cellular communication, with its extracellular accumulation triggering purinergic signaling cascades in a diversity of cell types. While the roles for purinergic signaling in health and disease have been well established, identification and differentiation of the specific mechanisms controlling cellular ATP release is less well understood. Multiple mechanisms have been proposed to regulate ATP release with connexin (Cx) hemichannels and pannexin (Panx) channels receiving major focus. However, segregating the specific roles of Panxs and Cxs in ATP release in a plethora of physiological and pathological contexts has remained enigmatic. This multifaceted problem has arisen from the selectivity of pharmacological inhibitors for Panxs and Cxs, methodological differences in assessing Panx and Cx function and the potential compensation by other isoforms in gene silencing and genetic knockout models. Consequently, there remains a void in the current understanding of specific contributions of Panxs and Cxs in releasing ATP during homeostasis and disease. Differentiating the distinct signaling pathways that regulate these two channels will advance our current knowledge of cellular communication and aid in the development of novel rationally-designed drugs for modulation of Panx and Cx activity, respectively.     

Exorcising the exocyst complex

The exocyst complex is an evolutionarily conserved multisubunit protein complex implicated in tethering secretory vesicles to the plasma membrane. Originally identified two decades ago in budding yeast, investigations using several different eukaryotic systems have since made great progress toward determination of the overall structure and organization of the eight exocyst subunits. Studies point to a critical role for the complex as a spatiotemporal regulator through the numerous protein and lipid interactions of its subunits, although a molecular understanding of exocyst function has been challenging to elucidate. Recent progress demonstrates that the exocyst is also important for additional trafficking steps and cellular processes beyond exocytosis, with links to development and disease. In this review, we discuss current knowledge of exocyst architecture, assembly, regulation and its roles in a variety of cellular trafficking pathways.     

EWSR1, a multifunctional protein,regulates cellular function and aging via genetic and epigenetic pathways

Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.     

Cellular signaling and biological functions of R-spondins

R-spondins (RSPOs) are a family of cysteine-rich secreted proteins containing a single thrombospondin type I repeat (TSR) domain. A vast amount of information regarding cellular signaling and biological functions of RSPOs has emerged over the last several years, especially with respect to their roles in the activation of the WNT signaling pathway. The identification of several classes of RSPO receptors may indicate that this family of proteins can affect several signaling cascades. Herein, we summarize the current understanding of RSPO signaling and its biological functions, and discuss its potential therapeutic implications to human diseases.     

LKB1, a protein kinase regulating cell proliferation and polarity

LKB1 is a serine-threonine protein kinase mutated in patients with an autosomal dominantly inherited cancer syndrome predisposing to multiple benign and malignant tumours, termed Peutz-Jeghers syndrome. Since its discovery in 1998, much research has focused on identification and characterisation of its cellular roles and analysing how LKB1 might be regulated. In this review we discuss exciting recent advances indicating that LKB1 functions as a tumour suppressor perhaps by controlling cell polarity. We also outline the current understanding of the molecular mechanisms by which LKB1 is regulated in vivo, through interaction with other proteins as well as by protein phosphorylation and prenylation.     

Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing,implications for Alzheimer's disease

Amyloid-β (Aβ) peptide accumulation in the brain is central to the pathogenesis of Alzheimer's disease (AD). Aβ is produced through proteolytic processing of a transmembrane protein, β-amyloid precursor protein (APP), by β- and γ-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Aβ. Members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apoER2, interact with APP and regulate its endocytic trafficking. Additionally, APP trafficking and processing are greatly affected by cellular cholesterol content. In this review, we summarize the current understanding of the roles of lipoprotein receptors and cholesterol in APP trafficking and processing and their implication for AD pathogenesis and therapy.     

Emerging from the Pak: the p21-activated protein kinase family

The p21-activated protein kinases (PAKs) are members of a growing family of regulatory enzymes that may play roles in diverse phenomena such as cellular morphogenesis, the stress response and the pathogenesis of AIDS. PAKs were initially discovered as binding partners for small (21 kDa) GTPases that regulate actin polymerization, and recent evidence has shown that some members of the PAK family may be effectors for related GTPases that are involved in intracellular vesicle trafficking. Because the downstream signalling pathways for all such GTPases are poorly understood, intense studies are under way to discern the role of PAK and its cousins. In this review, the authors highlight some of the established properties of the extended PAK family and discuss current controversies regarding their possible roles as GTPase effectors.     

Mitophagy: mechanisms, pathophysiological roles, and analysis

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.     

Genetic analysis of the cytoplasmic dynein subunit families

Cytoplasmic dyneins, the principal microtubule minus-end-directed motor proteins of the cell, are involved in many essential cellular processes. The major form of this enzyme is a complex of at least six protein subunits, and in mammals all but one of the subunits are encoded by at least two genes. Here we review current knowledge concerning the subunits, their interactions, and their functional roles as derived from biochemical and genetic analyses. We also carried out extensive database searches to look for new genes and to clarify anomalies in the databases. Our analysis documents evolutionary relationships among the dynein subunits of mammals and other model organisms, and sheds new light on the role of this diverse group of proteins, highlighting the existence of two cytoplasmic dynein complexes with distinct cellular roles.