scholarly journals Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses

2016 ◽  
Vol 27 (3) ◽  
pp. 572-587 ◽  
Author(s):  
Jing He ◽  
Jennifer L. Johnson ◽  
Jlenia Monfregola ◽  
Mahalakshmi Ramadass ◽  
Kersi Pestonjamasp ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Direct Evidence ◽  
Innate Immune ◽  
Cellular Functions ◽  
Late Endosomes ◽  
Endosomal Signaling ◽  
Endocytic Machinery ◽  
Live Cell Microscopy ◽  
And Function ◽  
Cell Microscopy

The molecular mechanisms that regulate late endosomal maturation and function are not completely elucidated, and direct evidence of a calcium sensor is lacking. Here we identify a novel mechanism of late endosomal maturation that involves a new molecular interaction between the tethering factor Munc13-4, syntaxin 7, and VAMP8. Munc13-4 binding to syntaxin 7 was significantly increased by calcium. Colocalization of Munc13-4 and syntaxin 7 at late endosomes was demonstrated by high-resolution and live-cell microscopy. Munc13-4–deficient cells show increased numbers of significantly enlarged late endosomes, a phenotype that was mimicked by the fusion inhibitor chloroquine in wild-type cells and rescued by expression of Munc13-4 but not by a syntaxin 7–binding–deficient mutant. Late endosomes from Munc13-4-KO neutrophils show decreased degradative capacity. Munc13-4–knockout neutrophils show impaired endosomal-initiated, TLR9-dependent signaling and deficient TLR9-specific CD11b up-regulation. Thus we present a novel mechanism of late endosomal maturation and propose that Munc13-4 regulates the late endocytic machinery and late endosomal–associated innate immune cellular functions.

scholarly journals Klp2 and Ase1 synergize to maintain meiotic spindle stability during metaphase I

2020 ◽  
Author(s):  
Fan Zheng ◽  
Fenfen Dong ◽  
Shuo Yu ◽  
Tianpeng Li ◽  
Yanze Jian ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Yeast Cells ◽  
Meiotic Spindle ◽  
Homologous Chromosomes ◽  
Spindle Dynamics ◽  
Live Cell Microscopy ◽  
Spindle Stability ◽  
Cell Microscopy ◽  
Mitosis And Meiosis ◽  
Meiosis I

ABSTRACTThe spindle apparatus segregates bi-oriented sister chromatids during mitosis but mono-oriented homologous chromosomes during meiosis I. It has remained unclear if similar molecular mechanisms operate to regulate spindle dynamics during mitosis and meiosis I. Here, we employed live-cell microscopy to compare the spindle dynamics of mitosis and meiosis I in fission yeast cells and demonstrated that the conserved kinesin-14 motor Klp2 plays a specific role in maintaining metaphase spindle length during meiosis I, but not during mitosis. Moreover, the maintenance of metaphase spindle stability during meiosis I requires the synergism between Klp2 and the conserved microtubule crosslinker Ase1 as the absence of both proteins causes exacerbated defects in metaphase spindle stability. The synergism is not necessary for regulating mitotic spindle dynamics. Hence, our work reveals a new molecular mechanism underlying meiotic spindle dynamics and provides insights into understanding differential regulation of meiotic and mitotic events.

Melanosomes on the move: a model to understand organelle dynamics

2011 ◽  
Vol 39 (5) ◽  
pp. 1191-1196 ◽  
Author(s):  
Alistair N. Hume ◽  
Miguel C. Seabra
Keyword(s):  
Intracellular Transport ◽  
Motor Proteins ◽  
Molecular Mechanisms ◽  
Pigment Cells ◽  
Future Prospects ◽  
Dynamic Nature ◽  
Live Cell Microscopy ◽  
Intracellular Organelles ◽  
Cell Microscopy ◽  
Shed Light

Advances in live-cell microscopy have revealed the extraordinarily dynamic nature of intracellular organelles. Moreover, movement appears to be critical in establishing and maintaining intracellular organization and organellar and cellular function. Motility is regulated by the activity of organelle-associated motor proteins, kinesins, dyneins and myosins, which move cargo along polar MT (microtubule) and actin tracks. However, in most instances, the motors that move specific organelles remain mysterious. Over recent years, pigment granules, or melanosomes, within pigment cells have provided an excellent model for understanding the molecular mechanisms by which motor proteins associate with and move intracellular organelles. In the present paper, we discuss recent discoveries that shed light on the mechanisms of melanosome transport and highlight future prospects for the use of pigment cells in unravelling general molecular mechanisms of intracellular transport.

scholarly journals Recent progress in research on molecular mechanisms of autophagy in the heart

2015 ◽  
Vol 308 (4) ◽  
pp. H259-H268 ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yun Chen ◽  
Mitsuaki Isobe ◽  
Åsa B. Gustafsson ◽  
Richard N. Kitsis ◽  
...  
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Degradation Process ◽  
Structure And Function ◽  
Cellular Functions ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Cellular Dysfunction

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

scholarly journals A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs

2021 ◽  
Vol 22 (17) ◽  
pp. 9535
Author(s):  
Yuhuai Xie ◽  
Yuanyuan Wei
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Innate Immune System ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Immune Mediated ◽  
Development And Differentiation ◽  
Non Coding Rnas ◽  
And Function

Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.

scholarly journals Sources and Remedies of Phototoxicity in Live Cell Microscopy

2000 ◽  
Vol 8 (4) ◽  
pp. 30-32
Author(s):  
Philip Hockberger
Keyword(s):  
Fluorescent Dyes ◽  
Imaging Techniques ◽  
Cell Types ◽  
Living Cells ◽  
Live Cell Microscopy ◽  
And Function ◽  
Cell Microscopy ◽  
Shed Light ◽  
Vexing Problem ◽  
Remarkable Progress

During the past decade there has been remarkable progress in understanding the behavior and function of biological cells. Progress was accelerated by the development of microscopic imaging techniques and fluorescent dyes that allowed investigators to visualize dynamic processes within subcellular compartments in heterogenous populations of living cells. These capabilities led to exciting new discoveries in cellular and molecular studies of a wide variety of cell types.Efforts to study living cells under microscopic conditions are not without problems, however. The most vexing problem is phototoxicity caused by either illumination alone (endogenous toxicity) or illumination of fluorescent dyes loaded into cells (exogenous toxicity). In this report I provide an overview of these general types of toxicity as well as describe recent results that may shed light on how to reduce them.

scholarly journals On the Wrong Track: Alterations of Ciliary Transport in Inherited Retinal Dystrophies

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Sánchez-Bellver ◽  
Vasileios Toulis ◽  
Gemma Marfany
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Molecular Mechanisms ◽  
Photoreceptor Cells ◽  
Cellular Functions ◽  
Inherited Disorders ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Elevated Protein ◽  
And Function

Ciliopathies are a group of heterogeneous inherited disorders associated with dysfunction of the cilium, a ubiquitous microtubule-based organelle involved in a broad range of cellular functions. Most ciliopathies are syndromic, since several organs whose cells produce a cilium, such as the retina, cochlea or kidney, are affected by mutations in ciliary-related genes. In the retina, photoreceptor cells present a highly specialized neurosensory cilium, the outer segment, stacked with membranous disks where photoreception and phototransduction occurs. The daily renewal of the more distal disks is a unique characteristic of photoreceptor outer segments, resulting in an elevated protein demand. All components necessary for outer segment formation, maintenance and function have to be transported from the photoreceptor inner segment, where synthesis occurs, to the cilium. Therefore, efficient transport of selected proteins is critical for photoreceptor ciliogenesis and function, and any alteration in either cargo delivery to the cilium or intraciliary trafficking compromises photoreceptor survival and leads to retinal degeneration. To date, mutations in more than 100 ciliary genes have been associated with retinal dystrophies, accounting for almost 25% of these inherited rare diseases. Interestingly, not all mutations in ciliary genes that cause retinal degeneration are also involved in pleiotropic pathologies in other ciliated organs. Depending on the mutation, the same gene can cause syndromic or non-syndromic retinopathies, thus emphasizing the highly refined specialization of the photoreceptor neurosensory cilia, and raising the possibility of photoreceptor-specific molecular mechanisms underlying common ciliary functions such as ciliary transport. In this review, we will focus on ciliary transport in photoreceptor cells and discuss the molecular complexity underpinning retinal ciliopathies, with a special emphasis on ciliary genes that, when mutated, cause either syndromic or non-syndromic retinal ciliopathies.

scholarly journals Pathophysiological Role of K2P Channels in Human Diseases

2021 ◽  
Vol 55 (S3) ◽  
pp. 65-86
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Ion Homeostasis ◽  
Human Diseases ◽  
Cellular Functions ◽  
Aberrant Expression ◽  
K2p Channels ◽  
And Function

The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.

scholarly journals A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution

2021 ◽  
Vol 11 ◽  
Author(s):  
Stephania Libreros ◽  
Ashley E. Shay ◽  
Robert Nshimiyimana ◽  
David Fichtner ◽  
Michael J. Martin ◽  
...  
Keyword(s):  
Eicosapentaenoic Acid ◽  
Direct Evidence ◽  
Ultra Violet ◽  
Innate Immune ◽  
Chromatographic Behavior ◽  
M2 Macrophage ◽  
Innate Immune Cells ◽  
Apoptotic Cells ◽  
And Function ◽  
Inflammation Resolution

The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.

scholarly journals Live imaging of single nuclear pores reveals unique assembly kinetics and mechanism in interphase

2010 ◽  
Vol 191 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Elisa Dultz ◽  
Jan Ellenberg
Keyword(s):  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Constant Rate ◽  
The Reformation ◽  
Assembly Kinetics ◽  
Live Cell Microscopy ◽  
Pore Complexes ◽  
Cell Microscopy

In metazoa, new nuclear pore complexes (NPCs) form at two different cell cycle stages: at the end of mitosis concomitant with the reformation of the nuclear envelope and during interphase. However, the mechanisms of these assembly processes may differ. In this study, we apply high resolution live cell microscopy to analyze the dynamics of single NPCs in living mammalian cells during interphase. We show that nuclear growth and NPC assembly are correlated and occur at a constant rate throughout interphase. By analyzing the kinetics of individual NPC assembly events, we demonstrate that they are initiated by slow accumulation of the membrane nucleoporin Pom121 followed by the more rapid association of the soluble NPC subcomplex Nup107–160. This inverse order of recruitment and the overall much slower kinetics compared with postmitotic NPC assembly support the conclusion that the two processes occur by distinct molecular mechanisms.

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