Chaperone-mediated autophagy: machinery,regulation and biological consequences

Degradation of dysfunctional intracellular components in the lysosome system can occur through three different pathways, i.e., macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). In this review, we focus on CMA, a type of autophagy distinct from the other two autophagic pathways owing to its selectivity, saturability and competitivity by which a subset of long-lived cytosolic soluble proteins are directly delivered into the lysosomal lumen via specific receptors. CMA participates in quality control to maintain normal cell functions by clearing “old” proteins and provides energy to cells under nutritional stress. Deregulation of CMA has recently been shown to underlie some diseases, especially neurodegenerative disorders for which the decline with age in the activity of CMA may become a major aggravating factor. Therefore, targeting aberrant alteration in CMA under pathological conditions could serve as a potential therapeutic strategy for treating related diseases.     

Viral journeys on the intracellular highways

Viruses are obligate intracellular pathogens that are dependent on cellular machineries for their replication. Recent technological breakthroughs have facilitated reliable identification of host factors required for viral infections and better characterization of the virus–host interplay. While these studies have revealed cellular machineries that are uniquely required by individual viruses, accumulating data also indicate the presence of broadly required mechanisms. Among these overlapping cellular functions are components of intracellular membrane trafficking pathways. Here, we review recent discoveries focused on how viruses exploit intracellular membrane trafficking pathways to promote various stages of their life cycle, with an emphasis on cellular factors that are usurped by a broad range of viruses. We describe broadly required components of the endocytic and secretory pathways, the Endosomal Sorting Complexes Required for Transport pathway, and the autophagy pathway. Identification of such overlapping host functions offers new opportunities to develop broad-spectrum host-targeted antiviral strategies.     

Mechanisms of ciliary targeting: entering importins and Rabs

Primary cilium is a rod-like plasma membrane protrusion that plays important roles in sensing the cellular environment and initiating corresponding signaling pathways. The sensory functions of the cilium critically depend on the unique enrichment of ciliary residents, which is maintained by the ciliary diffusion barrier. It is still unclear how ciliary cargoes specifically enter the diffusion barrier and accumulate within the cilium. In this review, the organization and trafficking mechanism of the cilium are compared to those of the nucleus, which are much better understood at the moment. Though the cilium differs significantly from the nucleus in terms of molecular and cellular functions, analogous themes and principles in the membrane organization and cargo trafficking are notable between them. Therefore, knowledge in the nuclear trafficking can likely shed light on our understanding of the ciliary trafficking. Here, with a focus on membrane cargoes in mammalian cells, we briefly review various ciliary trafficking pathways from the Golgi to the periciliary membrane. Models for the subsequent import translocation across the diffusion barrier and the enrichment of cargoes within the ciliary membrane are discussed in detail. Based on recent discoveries, we propose a Rab–importin-based model in an attempt to accommodate various observations on ciliary targeting.     

Dissecting the biochemical architecture and morphological release pathways of the human platelet extracellular vesiculome

Platelet extracellular vesicles (PEVs) have emerged as potential mediators in intercellular communication. PEVs exhibit several activities with pathophysiological importance and may serve as diagnostic biomarkers. Here, imaging and analytical techniques were employed to unveil morphological pathways of the release, structure, composition, and surface properties of PEVs derived from human platelets (PLTs) activated with the thrombin receptor activating peptide (TRAP). Based on extensive electron microscopy analysis, we propose four morphological pathways for PEVs release from TRAP-activated PLTs: (1) plasma membrane budding, (2) extrusion of multivesicular α-granules and cytoplasmic vacuoles, (3) plasma membrane blistering and (4) “pearling” of PLT pseudopodia. The PLT extracellular vesiculome encompasses ectosomes, exosomes, free mitochondria, mitochondria-containing vesicles, “podiasomes” and PLT “ghosts”. Interestingly, a flow cytometry showed a population of TOM20⁺LC3⁺ PEVs, likely products of platelet mitophagy. We found that lipidomic and proteomic profiles were different between the small PEV (S-PEVs; mean diameter 103 nm) and the large vesicle (L-PEVs; mean diameter 350 nm) fractions separated by differential centrifugation. In addition, the majority of PEVs released by activated PLTs was composed of S-PEVs which have markedly higher thrombin generation activity per unit of PEV surface area compared to L-PEVs, and contribute approximately 60% of the PLT vesiculome procoagulant potency.     

Neuronal ciliary signaling in homeostasis and disease

Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders. Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations. Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative functions and roles in human diseases.     

Lipid droplet dynamics in budding yeast

Eukaryotic cells store excess fatty acids as neutral lipids, predominantly triacylglycerols and sterol esters, in organelles termed lipid droplets (LDs) that bulge out from the endoplasmic reticulum. LDs are highly dynamic and contribute to diverse cellular functions. The catabolism of the storage lipids within LDs is channeled to multiple metabolic pathways, providing molecules for energy production, membrane building blocks, and lipid signaling. LDs have been implicated in a number of protein degradation and pathogen infection processes. LDs may be linked to prevalent human metabolic diseases and have marked potential for biofuel production. The knowledge accumulated on LDs in recent years provides a foundation for diverse, and even unexpected, future research. This review focuses on recent advances in LD research, emphasizing the diverse physiological roles of LDs in the model system of budding yeast.     

Rab protein evolution and the history of the eukaryotic endomembrane system

Spectacular increases in the quantity of sequence data genome have facilitated major advances in eukaryotic comparative genomics. By exploiting homology with classical model organisms, this makes possible predictions of pathways and cellular functions currently impossible to address in intractable organisms. Echoing realization that core metabolic processes were established very early following evolution of life on earth, it is now emerging that many eukaryotic cellular features, including the endomembrane system, are ancient and organized around near-universal principles. Rab proteins are key mediators of vesicle transport and specificity, and via the presence of multiple paralogues, alterations in interaction specificity and modification of pathways, contribute greatly to the evolution of complexity of membrane transport. Understanding system-level contributions of Rab proteins to evolutionary history provides insight into the multiple processes sculpting cellular transport pathways and the exciting challenges that we face in delving further into the origins of membrane trafficking specificity.     

The function of miRNA in cardiac hypertrophy

Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and non-cardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed.     

Spectrin-based skeleton as an actor in cell signaling

This review focuses on the recent advances in functions of spectrins in non-erythroid cells. We discuss new data concerning the commonly known role of the spectrin-based skeleton in control of membrane organization, stability and shape, and tethering protein mosaics to the cellular motors and to all major filament systems. Particular effort has been undertaken to highlight recent advances linking spectrin to cell signaling phenomena and its participation in signal transduction pathways in many cell types.     

Sumoylation regulates diverse biological processes

Ten years after its discovery, the small ubiquitin-like protein modifier (SUMO) has emerged as a key regulator of proteins. While early studies indicated that sumoylation takes place mainly in the nucleus, an increasing number of non-nuclear substrates have recently been identified, suggesting a wider stage for sumoylation in the cell. Unlike ubiquitylation, which primarily targets a substrate for degradation, sumoylation regulates a substrate’s functions mainly by altering the intracellular localization, protein-protein interactions or other types of post-translational modifications. These changes in turn affect gene expression, genomic and chromosomal stability and integrity, and signal transduction. Sumoylation is counter-balanced by desumoylation, and well-balanced sumoylation is essential for normal cellular behaviors. Loss of the balance has been associated with a number of diseases. This paper reviews recent progress in the study of SUMO pathways, substrates, and cellular functions and highlights important findings that have accelerated advances in this study field and link sumoylation to human diseases. Received 19 March 2007; received after version 16 July 2007; accepted 1 August 2007     

Current knowledge on exosome biogenesis and release

Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.     

Farnesoid X receptor alpha: a molecular link between bile acids and steroid signaling?

Bile acids are cholesterol metabolites that have been extensively studied in recent decades. In addition to having ancestral roles in digestion and fat solubilization, bile acids have recently been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor farnesoid X receptor (FXRα) or of the G protein-coupled receptor TGR5. In this review, we will focus on the emerging role of FXRα, suggesting important functions for the receptor in steroid metabolism. It has been described that FXRα is expressed in the adrenal glands and testes, where it seems to control steroid production. FXRα also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors. In this review, we discuss the potential impacts of bile acid (BA), through its interactions with steroid metabolism, on glucose metabolism, sexual function, and prostate and breast cancers. Although several of the published reports rely on in vitro studies, they highlight the need to understand the interactions that may affect health. This effect is important because BA levels are increased in several pathophysiological conditions related to liver injuries. Additionally, BA receptors are targeted clinically using therapeutics to treat liver diseases, diabetes, and cancers.     

Biogenesis of bacterial inner-membrane proteins

All cells must traffic proteins into and across their membranes. In bacteria, several pathways have evolved to enable protein transfer across the inner membrane, the periplasm, and the outer membrane. The major route of protein translocation in and across the cytoplasmic membrane is the general secretion pathway (Sec-pathway). The biogenesis of membrane proteins not only requires protein translocation but also coordinated targeting to the membrane beforehand and folding and assembly into their protein complexes afterwards to function properly in the cell. All these processes are responsible for the biogenesis of membrane proteins that mediate essential functions of the cell such as selective transport, energy conversion, cell division, extracellular signal sensing, and motility. This review will highlight the most recent developments on the structure and function of bacterial membrane proteins, focusing on the journey that integral membrane proteins take to find their final destination in the inner membrane.     

Organization of the multifunctional neural network regulating visceral organs inHelix pomatia L (Mollusca,Gastropoda)

Summary InHelix pomatia L. the overlapping neuronal network was found to regulate the visceral functions (e.g. cardiorenal, respiratory and genital functions). The neural network is organized around the multifunctional interneurons, which take part in forming both afferent and efferent pathways. The interneurons are sensitive to a wide range of neurotransmitters or transmitter candidates including low molecular weight substances (ACh, 5HT, DA, octopamine, glutamate) and several oligopeptides. In this system both selection of information and modification of membrane properties (for example habituation) are carried out by a combination of simultaneously liberated active agents.     

Annexins as organizers of cholesterol- and sphingomyelin-enriched membrane microdomains in Niemann-Pick type C disease

Growing evidence suggests that membrane microdomains enriched in cholesterol and sphingomyelin are sites for numerous cellular processes, including signaling, vesicular transport, interaction with pathogens, and viral infection, etc. Recently some members of the annexin family of conserved calcium and membrane-binding proteins have been recognized as cholesterol-interacting molecules and suggested to play a role in the formation, stabilization, and dynamics of membrane microdomains to affect membrane lateral organization and to attract other proteins and signaling molecules onto their territory. Furthermore, annexins were implicated in the interactions between cytosolic and membrane molecules, in the turnover and storage of cholesterol and in various signaling pathways. In this review, we focus on the mechanisms of interaction of annexins with lipid microdomains and the role of annexins in membrane microdomains dynamics including possible participation of the domain-associated forms of annexins in the etiology of human lysosomal storage disease called Niemann-Pick type C disease, related to the abnormal storage of cholesterol in the lysosome-like intracellular compartment. The involvement of annexins and cholesterol/sphingomyelin-enriched membrane microdomains in other pathologies including cardiac dysfunctions, neurodegenerative diseases, obesity, diabetes mellitus, and cancer is likely, but is not supported by substantial experimental observations, and therefore awaits further clarification.     

The primary cilium as a dual sensor of mechanochemical signals in chondrocytes

The primary cilium is an immotile, solitary, and microtubule-based structure that projects from cell surfaces into the extracellular environment. The primary cilium functions as a dual sensor, as mechanosensors and chemosensors. The primary cilia coordinate several essential cell signaling pathways that are mainly involved in cell division and differentiation. A primary cilium malfunction can result in several human diseases. Mechanical loading is sense by mechanosensitive cells in nearly all tissues and organs. With this sensation, the mechanical signal is further transduced into biochemical signals involving pathways such as Akt, PKA, FAK, ERK, and MAPK. In this review, we focus on the fundamental functional and structural features of primary cilia in chondrocytes and chondrogenic cells.     

Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer

TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL’s ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL’s potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents.