scholarly journals Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway

2020 ◽  
Author(s):  
Sydney E. Cason ◽  
Peter Carman ◽  
Claire Van Duyne ◽  
Juliet Goldsmith ◽  
Roberto Dominguez ◽  
...  
Keyword(s):  
Axon Terminal ◽  
Effector Proteins ◽  
Primary Neurons ◽  
Degradative Pathway ◽  
Neuronal Homeostasis ◽  
Maturation State ◽  
And Function ◽  
Dynactin Complex ◽  
Dependent Pathway

AbstractAutophagy is a degradative pathway required to maintain neuronal homeostasis. Neuronal autophagosomes form constitutively at the axon terminal and mature via lysosomal fusion during dynein-mediated transport to the soma. How the dynein-autophagosome interaction is regulated during maturation is unknown. Here, we identify a series of handoffs between dynein effectors as autophagosomes transit along the axons of primary neurons. In the distal axon, JIP1 initiates autophagosomal transport, while autophagosomes in the mid-axon require HAP1 and Huntingtin for motility. We demonstrate that HAP1 is a bonafide dynein activator, binding the dynein-dynactin complex via canonical and noncanonical interactions. JIP3 is found on most axonal autophagosomes but specifically regulates the transport of acidified autolysosomes. Inhibiting autophagosomal transport disrupts maturation, while inhibiting autophagosomal maturation perturbs the association and function of dynein effectors. Thus maturation and transport are tightly linked. These results describe a novel maturation-based dynein effector handoff on neuronal autophagosomes that is key to autophagosomal motility, cargo degradation, and the maintenance of axonal health.SummaryNeuronal autophagosomes form in the distal axon and mature via fusion with lysosomes during their dynein-driven transport to the soma. Dynein is regulated on autophagosomes by distinct effector proteins—JIP1, HAP1, and JIP3—depending on location and autophagosomal maturity. In this sequential pathway, transport and maturation state are tightly linked to maintain neuronal health.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

scholarly journals Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins

2020 ◽  
Vol 8 (12) ◽  
pp. 1976
Author(s):  
Yoshiyuki Hakata ◽  
Masaaki Miyazawa
Keyword(s):  
Molecular Mechanisms ◽  
Restriction Factors ◽  
Mrna Editing ◽  
Antiviral Function ◽  
Apobec3 Proteins ◽  
And Function ◽  
Editing Enzyme ◽  
Dependent Pathway ◽  
Independent Mode ◽  
Human Apobec3g

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) proteins (APOBEC3s) are deaminases that convert cytosines to uracils predominantly on a single-stranded DNA, and function as intrinsic restriction factors in the innate immune system to suppress replication of viruses (including retroviruses) and movement of retrotransposons. Enzymatic activity is supposed to be essential for the APOBEC3 antiviral function. However, it is not the only way that APOBEC3s exert their biological function. Since the discovery of human APOBEC3G as a restriction factor for HIV-1, the deaminase-independent mode of action has been observed. At present, it is apparent that both the deaminase-dependent and -independent pathways are tightly involved not only in combating viruses but also in human tumorigenesis. Although the deaminase-dependent pathway has been extensively characterized so far, understanding of the deaminase-independent pathway remains immature. Here, we review existing knowledge regarding the deaminase-independent antiretroviral functions of APOBEC3s and their molecular mechanisms. We also discuss the possible unidentified molecular mechanism for the deaminase-independent antiretroviral function mediated by mouse APOBEC3.

scholarly journals Role of Axonal Odorant Receptors in Olfactory Topography

2020 ◽  
Vol 15 ◽  
pp. 263310552092341
Author(s):  
Claudia Lodovichi
Keyword(s):  
Olfactory Bulb ◽  
Sensory Neurons ◽  
Axon Terminal ◽  
Internal Representation ◽  
Dual Role ◽  
Odorant Receptors ◽  
Topographic Map ◽  
And Function ◽  
Guidance Molecule

A unique feature in the organization of the olfactory system is the dual role of the odorant receptors: they detect odors in the nasal epithelium and they play an instructive role in the convergence of olfactory sensory neuron axons in specific loci, ie, glomeruli, in the olfactory bulb. The dual role is corroborated by the expression of the odorant receptors in 2 specific locations of the olfactory sensory neurons: the cilia that protrude in the nostril, where the odorant receptors interact with odors, and the axon terminal, a suitable location for a potential axon guidance molecule. The mechanism of activation and function of the odorant receptors expressed at the axon terminal remained unknown for almost 20 years. A recent study identified the first putative ligand of the axonal odorant receptors, phosphatidylethanolamine-binding protein1, a molecule expressed in the olfactory bulb. The distinctive mechanisms of activation of the odorant receptors expressed at the opposite locations in sensory neurons, by odors, at the cilia, and by molecules expressed in the olfactory bulb, at the axon terminal, explain the dual role of the odorant receptors and link the specificity of odor perception with its internal representation, in the topographic map.

scholarly journals Neuron-based high-content assay and screen for CNS active mitotherapeutics

2020 ◽  
Vol 6 (2) ◽  
pp. eaaw8702 ◽  
Author(s):  
Boglarka H. Varkuti ◽  
Miklos Kepiro ◽  
Ze Liu ◽  
Kyle Vick ◽  
Yosef Avchalumov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hippocampal Neurons ◽  
Mitochondrial Dynamics ◽  
Synaptic Activity ◽  
Glutamate Toxicity ◽  
Primary Neurons ◽  
Screening Assay ◽  
Dynamics And Function ◽  
Small Molecule Modulators ◽  
And Function

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

scholarly journals The periplasmic chaperone Skp is required for successful Salmonella Typhimurium infection in a murine typhoid model

Microbiology ◽  
2011 ◽  
Vol 157 (3) ◽  
pp. 848-858 ◽  
Author(s):  
Gary Rowley ◽  
Henrieta Skovierova ◽  
Andrew Stevenson ◽  
Bronislava Rezuchova ◽  
Dagmar Homerova ◽  
...  
Keyword(s):  
Essential Gene ◽  
Outer Membrane Proteins ◽  
Polymyxin B ◽  
Effector Proteins ◽  
Upstream Gene ◽  
Increased Sensitivity ◽  
Periplasmic Chaperone ◽  
And Function

The alternative sigma factor σ E (rpoE) is essential for survival in vivo of Salmonella Typhimurium but is dispensable during growth in the laboratory. We have been identifying σ E-regulated genes and studying their regulation and function to elucidate their potential role in the severe attenuation of S. Typhimurium rpoE mutants. In this study we identify five promoters that control the rseP, yaeT (bamA), skp region. A confirmed σ E-dependent promoter, yaeTp1, and a second downstream promoter, yaeTp2, are located within the upstream gene rseP and direct expression of the downstream genes. The only known function of RseP is σ E activation, and it is therefore not expected to be essential for S. Typhimurium in vitro. However, it proved impossible to delete the entire rseP gene due to the presence of internal promoters that regulate the essential gene yaeT. We could inactivate rseP by deleting the first third of the gene, leaving the yaeT promoters intact. Like the rpoE mutant, the rseP mutant exhibited severe attenuation in vivo. We were able to delete the entire coding sequence of skp, which encodes a periplasmic chaperone involved in targeting misfolded outer-membrane proteins to the β-barrel assembly machinery. The skp mutant was attenuated in mice after oral and parenteral infection. Virulence could be complemented by providing skp in trans but only by linking it to a heterologous σ E-regulated promoter. The reason the skp mutant is attenuated is currently enigmatic, but we know it is not through increased sensitivity to a variety of RpoE-activating host stresses, such as H2O2, polymyxin B and high temperature, or through altered secretion of effector proteins by either the Salmonella pathogenicity island (SPI)-1 or the SPI-2 type III secretion system.

scholarly journals A TRPC1 Protein-dependent Pathway Regulates Osteoclast Formation and Function

2013 ◽  
Vol 288 (31) ◽  
pp. 22219-22232 ◽  
Author(s):  
E-Ching Ong ◽  
Vasyl Nesin ◽  
Courtney L. Long ◽  
Chang-Xi Bai ◽  
Jan L. Guz ◽  
...  
Keyword(s):  
Osteoclast Formation ◽  
And Function ◽  
Dependent Pathway

scholarly journals Extracellular Vesicles promote host immunity during an M. tuberculosis infection through RNA Sensing

2018 ◽  
Author(s):  
Yong Cheng ◽  
Jeffery S. Schorey
Keyword(s):  
Extracellular Vesicles ◽  
Type I ◽  
Dependent Manner ◽  
Drug Resistant ◽  
Interferon Production ◽  
Bacterial Killing ◽  
Novel Approach ◽  
And Function ◽  
Dependent Pathway

AbstractExtracellular vesicles (EVs) have been shown to carry microbial components and function in the host defense against infections. In this study, we demonstrate that Mycobacterium tuberculosis (M.tb) RNA is delivered into macrophage-derived EVs through an M.tb SecA2-dependent pathway, and that EVs released from M.tb-infected macrophages stimulate a host RIG-I/MAVS/TBK1/IRF3 RNA sensing pathway, leading to type I interferon production in recipient cells. These EVs also promote, in a RIG-I/MAVS-dependent manner, the maturation of M.tb-containing phagosomes through a noncanonical LC3 modification, leading to increased bacterial killing. Moreover, treatment of M.tb-infected macrophages or mice with a combination of moxifloxacin and EVs, isolated from M.tb-infected macrophages, significantly lowered bacterial burden relative to either treatment alone. We propose that EVs, which are preferentially removed by macrophages in vivo, may be developed in combination with effective antibiotics as a novel approach to treat drug-resistant TB.

scholarly journals Glycan analysis of human neutrophil granules implicates a maturation-dependent glycosylation machinery

2020 ◽  
Vol 295 (36) ◽  
pp. 12648-12660 ◽  
Author(s):  
Vignesh Venkatakrishnan ◽  
Régis Dieckmann ◽  
Ian Loke ◽  
Harry C. Tjondro ◽  
Sayantani Chatterjee ◽  
...  
Keyword(s):  
Gradient Centrifugation ◽  
Effector Proteins ◽  
Protein Glycosylation ◽  
Sialyl Lewis X ◽  
Human Neutrophils ◽  
Immune Functions ◽  
Lewis X ◽  
Percoll Density Gradient Centrifugation ◽  
Percoll Density Gradient ◽  
And Function

Protein glycosylation is essential to trafficking and immune functions of human neutrophils. During granulopoiesis in the bone marrow, distinct neutrophil granules are successively formed. Distinct receptors and effector proteins, many of which are glycosylated, are targeted to each type of granule according to their time of expression, a process called “targeting by timing.” Therefore, these granules are time capsules reflecting different times of maturation that can be used to understand the glycosylation process during granulopoiesis. Herein, neutrophil subcellular granules were fractionated by Percoll density gradient centrifugation, and N- and O-glycans present in each compartment were analyzed by LC–MS. We found abundant paucimannosidic N-glycans and lack of O-glycans in the early-formed azurophil granules, whereas the later-formed specific and gelatinase granules and secretory vesicles contained complex N- and O-glycans with remarkably elongated N-acetyllactosamine repeats with Lewis epitopes. Immunoblotting and histochemical analysis confirmed the expression of Lewis X and sialyl-Lewis X in the intracellular granules and on the cell surface, respectively. Many glycans identified are unique to neutrophils, and their complexity increased progressively from azurophil granules to specific granules and then to gelatinase granules, suggesting temporal changes in the glycosylation machinery indicative of “glycosylation by timing” during granulopoiesis. In summary, this comprehensive neutrophil granule glycome map, the first of its kind, highlights novel granule-specific glycosylation features and is a crucial first step toward a better understanding of the mechanisms regulating protein glycosylation during neutrophil granulopoiesis and a more detailed understanding of neutrophil biology and function.

scholarly journals Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis

Blood ◽  
2017 ◽  
Vol 130 (18) ◽  
pp. 1965-1975 ◽  
Author(s):  
Juan R. Alvarez-Dominguez ◽  
Harvey F. Lodish
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Noncoding Rna ◽  
Effector Proteins ◽  
Protein Targets ◽  
Ability To Act ◽  
Coordinate Gene Expression ◽  
Multiple Levels ◽  
And Function ◽  
Influence Gene Expression

Abstract Long noncoding RNAs (lncRNAs) are increasingly recognized as vital components of gene programs controlling cell differentiation and function. Central to their functions is an ability to act as scaffolds or as decoys that recruit or sequester effector proteins from their DNA, RNA, or protein targets. lncRNA-modulated effectors include regulators of transcription, chromatin organization, RNA processing, and translation, such that lncRNAs can influence gene expression at multiple levels. Here we review the current understanding of how lncRNAs help coordinate gene expression to modulate cell fate in the hematopoietic system. We focus on a growing number of mechanistic studies to synthesize emerging principles of lncRNA function, emphasizing how they facilitate diversification of gene programming during development. We also survey how disrupted lncRNA function can contribute to malignant transformation, highlighting opportunities for therapeutic intervention in specific myeloid and lymphoid cancers. Finally, we discuss challenges and prospects for further elucidation of lncRNA mechanisms.

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