scholarly journals Retromer has a selective function in cargo sorting via endosome transport carriers

2018 ◽  
Vol 218 (2) ◽  
pp. 615-631 ◽  
Author(s):  
Yi Cui ◽  
Julian M. Carosi ◽  
Zhe Yang ◽  
Nicholas Ariotti ◽  
Markus C. Kerr ◽  
...  
Keyword(s):  
Vesicular Trafficking ◽  
Lysosomal Hydrolases ◽  
Cell Level ◽  
Ultrastructural Alteration ◽  
Membrane Protein Complex ◽  
Lysosomal Function ◽  
Trafficking Pathway ◽  
Peripheral Membrane Protein ◽  
And Function ◽  
Proteolytic Capacity

Retromer is a peripheral membrane protein complex that coordinates multiple vesicular trafficking events within the endolysosomal system. Here, we demonstrate that retromer is required for the maintenance of normal lysosomal morphology and function. The knockout of retromer subunit Vps35 causes an ultrastructural alteration in lysosomal structure and aberrant lysosome function, leading to impaired autophagy. At the whole-cell level, knockout of retromer Vps35 subunit reduces lysosomal proteolytic capacity as a consequence of the improper processing of lysosomal hydrolases, which is dependent on the trafficking of the cation-independent mannose 6-phosphate receptor (CI-M6PR). Incorporation of CI-M6PR into endosome transport carriers via a retromer-dependent process is restricted to those tethered by GCC88 but not golgin-97 or golgin-245. Finally, we show that this retromer-dependent retrograde cargo trafficking pathway requires SNX3, but not other retromer-associated cargo binding proteins, such as SNX27 or SNX-BAR proteins. Therefore, retromer does contribute to the retrograde trafficking of CI-M6PR required for maturation of lysosomal hydrolases and lysosomal function.

Congenital neutropenia

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 344-350 ◽  
Author(s):  
Christoph Klein
Keyword(s):  
Ribosomal Proteins ◽  
Mitochondrial Proteins ◽  
Phenotypic Traits ◽  
Genetic Defects ◽  
Congenital Neutropenia ◽  
Lysosomal Function ◽  
Genes Encoding ◽  
And Function ◽  
Neutrophil Differentiation ◽  
Remarkable Progress

Abstract Congenital neutropenia comprises a variety of genetically heterogeneous phenotypic traits. Molecular elucidation of the underlying genetic defects has yielded important insights into the physiology of neutrophil differentiation and function. Non-syndromic variants of congenital neutropenia are caused by mutations in ELA2, HAX1, GFI1, or WAS. Syndromic variants of congenital neutropenia may be due to mutations in genes controlling glucose metabolism (SLC37A4, G6PC3) or lysosomal function (LYST, RAB27A, ROBLD3/p14, AP3B1, VPS13B). Furthermore, defects in genes encoding ribosomal proteins (SBDS, RMRP) and mitochondrial proteins (AK2, TAZ) are associated with congenital neutropenia syndromes. Despite remarkable progress in the field, many patients with congenital neutropenia cannot yet definitively be classified by genetic terms. This review addresses diagnostic and therapeutic aspects of congenital neutropenia and covers recent molecular and pathophysiological insights of selected congenital neutropenia syndromes.

scholarly journals INPP4B promotes leukemia by restricting leukemic stem cell differentiation through regulation of lysosomal functions

2021 ◽  
Author(s):  
John F. Woolley ◽  
Keyue Chen ◽  
Gizem E. Genc ◽  
Daniel K.C. Lee ◽  
Irakli Dzneladze ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Gene Networks ◽  
Stem Cell Differentiation ◽  
Leukemic Stem Cell ◽  
Lysosomal Function ◽  
Proteolytic Capacity ◽  
Lysosomal Gene

Despite an increased understanding of leukemogenesis, specific mechanisms that underlie stemness in leukemia remain largely undefined. Here, we report a novel pathway which regulates leukemic differentiation through control of lysosomal biology. We show that disruption of INPP4B results in dysregulated lysosomal gene networks, reduced lysosomal numbers and proteolytic capacity in leukemia. Inpp4b-deficient HSCs and LSCs are functionally compromised. Inpp4b-deficient leukemia models develop more differentiated leukemias with reduced disease initiating potential, and improved overall survival compared to Inpp4b-expressing leukemias. Together, our data is consistent with a model where INPP4B restricts differentiation of LSCs through regulation of lysosomal function. These data provide a mechanism to explain the association of INPP4B with aggressive AML and highlight avenues for LSC-specific leukemia therapies.

scholarly journals Rab GTPases in Osteoclastic Bone Resorption and Autophagy

2020 ◽  
Vol 21 (20) ◽  
pp. 7655
Author(s):  
Michèle Roy ◽  
Sophie Roux
Keyword(s):  
Bone Resorption ◽  
Molecular Mechanisms ◽  
Bone Diseases ◽  
Vesicular Trafficking ◽  
Disease Development ◽  
Rab Gtpases ◽  
Bone Homeostasis ◽  
Autophagic Degradation ◽  
Ruffled Border ◽  
And Function

Small guanosine triphosphate hydrolases (GTPases) of the Rab family are involved in plasma membrane delivery, fusion events, and lysosomal and autophagic degradation pathways, thereby regulating signaling pathways and cell differentiation and function. Osteoclasts are bone-resorbing cells that maintain bone homeostasis. Polarized vesicular trafficking pathways result in the formation of the ruffled border, the osteoclast’s resorptive organelle, which also assists in transcytosis. Here, we reviewed the different roles of Rab GTPases in the endomembrane machinery of osteoclasts and in bone diseases caused by the dysfunction of these proteins, with a particular focus on autophagy and bone resorption. Understanding the molecular mechanisms underlying osteoclast-related bone disease development is critical for developing and improving therapies.

scholarly journals Mitochondrial isolation: when size matters

2020 ◽  
Vol 5 ◽  
pp. 226
Author(s):  
Alexander G. Bury ◽  
Amy E. Vincent ◽  
Doug M. Turnbull ◽  
Paolo Actis ◽  
Gavin Hudson
Keyword(s):  
Mitochondrial Dysfunction ◽  
Single Cell ◽  
Cellular Heterogeneity ◽  
Single Cell Level ◽  
Cell Level ◽  
Isolation Techniques ◽  
Cellular Environment ◽  
Dynamics And Function ◽  
And Function ◽  
Subcellular Resolution

Mitochondrial vitality is critical to cellular function, with mitochondrial dysfunction linked to a growing number of human diseases. Tissue and cellular heterogeneity, in terms of genetics, dynamics and function means that increasingly mitochondrial research is conducted at the single cell level. Whilst, there are several single-cell technologies that are currently available, each with their advantages, they cannot be easily adapted to study mitochondria with subcellular resolution. Here we review the current techniques and strategies for mitochondrial isolation, critically discussing each technology’s limitations for future mitochondrial research. Finally, we highlight and discuss the recent breakthroughs in sub-cellular isolation techniques, with a particular focus on nanotechnologies that enable the isolation of mitochondria, from subcellular compartments, with unprecedented spatial precision with minimal disruption to mitochondria and their immediate cellular environment.

scholarly journals Disruption of vacuolin microdomains in the host Dictyostelium discoideum increases resistance to Mycobacterium marinum-induced membrane damage and infection

2021 ◽  
Author(s):  
Cristina Bosmani ◽  
Angélique Perret ◽  
Florence Leuba ◽  
Aurélie Guého ◽  
Nabil Hanna ◽  
...  
Keyword(s):  
Dictyostelium Discoideum ◽  
Membrane Damage ◽  
Mycobacterium Marinum ◽  
Vesicular Trafficking ◽  
Membrane Microdomains ◽  
Membrane Association ◽  
Phagosome Maturation ◽  
Closely Related Species ◽  
Important Host ◽  
And Function

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, manipulates the host phagosome maturation pathway to replicate intracellularly. Mycobacterium marinum, a closely-related species, and Dictyostelium discoideum, a social amoeba and alternative phagocytic host, have been used as models to study host-pathogen interactions occurring during mycobacterial infections. Vacuolins, functional homologues of the mammalian flotillins, organize membrane microdomains and play a role in vesicular trafficking. Various pathogens have been reported to manipulate their membrane association and function. During infection of D. discoideum with M. marinum, Vacuolin C was specifically and highly induced and all three vacuolin isoforms were enriched at the mycobacteria-containing-vacuole (MCV). In addition, absence of vacuolins reduced escape from the MCV and conferred resistance to M. marinum infection. Moreover, ESAT-6, the membrane-disrupting virulence factor of M. marinum, was less associated with membranes when vacuolins were absent. Together, these results suggest that vacuolins are important host factors that are manipulated by mycobacteria to inflict membrane damage and escape from their compartment.

scholarly journals Single-cell RNA-Seq reveals the link between CD45 isoforms and tumor-infiltrating T cells heterogeneity in liver cancer

2020 ◽  
Author(s):  
Biaofeng Zhou ◽  
Shang Liu ◽  
Liang Wu ◽  
Yan Sun ◽  
Jie Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Single Cell ◽  
Cell Function ◽  
Effector Memory ◽  
Single Cell Level ◽  
Cell Level ◽  
Cd45 Isoforms ◽  
And Function

AbstractCD45 isoforms play a major role in characterizing T cell function, phenotype, and development. However, there is lacking comprehensive interrogation about the relationship between CD45 isoforms and T lymphocytes from cancer patients at the single-cell level yet. Here, we investigated the CD45 isoforms component of published 5,063 T cells of hepatocellular carcinoma (HCC), which has been assigned functional states. We found that the distribution of CD45 isoforms in T lymphocytes cells depended on tissue resource, cell type, and functional state. Further, we demonstrated that CD45RO and CD45RA dominate in characterizing the phenotype and function of T cell though multiple CD45 isoforms coexist in T cells, through a novel alternative splicing pattern analysis. We identified a novel development trajectory of tumor-infiltrating T cells from Tcm to Temra (effector memory T cells re-expresses CD45RA) after detecting two subpopulations in state of transition, Tcm (central memory T) and Tem (effector memory T). Temra, capable of high cytotoxic characteristics, was discovered to be associated with the stage of HCC and may be a target of immunotherapy. Our study presents a comprehension of the connection between CD45 isoforms and the function, states, sources of T lymphocytes cells in HCC patients at the single-cell level, providing novel insight for the effect of CD45 isoforms on T cell heterogeneity.

scholarly journals PIKfyve inhibition reveals a novel role for Inpp4b in the regulation of PtdIns(3)P and lysosome dynamics

2021 ◽  
Author(s):  
Golam T. Saffi ◽  
Emily Mangialardi ◽  
Jean Vacher ◽  
Roberto J. Botelho ◽  
LEONARDO SALMENA
Keyword(s):  
Autophagic Flux ◽  
Contributing Factors ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Lipid Kinase ◽  
Lysosomal Function ◽  
Cargo Delivery ◽  
Simultaneous Inhibition ◽  
And Function ◽  
Underlying Processes

Lysosome membranes contain diverse phosphoinositide (PtdIns) lipids that co-ordinate lysosome function and dynamics. The PtdIns repertoire on lysosomes is tightly regulated by the action of diverse PtdIns kinases and phosphatases. Specific roles for PtdIns in lysosomal function and dynamics are currently unclear and require further investigation. PIKfyve, a lipid kinase which synthesizes PtdIns(3,5)P2 from PtdIns(3)P, controls lysosome fusion-fission cycles, autophagosome turnover and endocytic cargo delivery. We have recently characterized a role for INPP4B, a PtdIns phosphatase which hydrolyses PtdIns(3,4)P2 to form PtdIns(3)P, in the regulation of lysosomal biogenesis and function. To gain a better understanding of PtdIns homeostasis on lysosomes, we investigated the consequence of disrupting PIKfyve in Inpp4b-deficient mouse embryonic fibroblasts. Surprisingly, simultaneous inhibition of Inpp4b and PIKfyve functions impair lysosome fission and exacerbate lysosome enlargement and inhibit autophagic flux. Further examination into the underlying processes that may explain exaggerated lysosome enlargement revealed elevated levels of lysosome-associated PtdIns(3)P as contributing factors that control lysosome morphology in cells where Inpp4b and PIKfyve are disrupted. Overall, our study suggests that lysosomal functions are regulated by Inpp4b, through a paradoxical role in suppressing the induction of PtdIns(3)P production.

scholarly journals Acidic Compartment Size, Positioning, and Function during Myogenesis and Their Modulation by the Wnt/Beta-Catenin Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Kayo M. Bagri ◽  
Ivone A. Rosa ◽  
Stephany Corrêa ◽  
Aline Yamashita ◽  
José Brito ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Muscle Cells ◽  
Beta Catenin ◽  
Inhibitory Effects ◽  
Lysosomal Function ◽  
Acidic Compartment ◽  
And Function ◽  
Cellular Compartments ◽  
Acidic Compartments

Lysosomes and acidic compartments are involved in breaking down of macromolecules, membrane recycling, and regulation of signaling pathways. Here, we analyzed the role of acidic compartments during muscle differentiation and the involvement of the Wnt/beta-catenin pathway in lysosomal function during myogenesis. Acridine orange was used to localize and quantify acidic cellular compartments in primary cultures of embryonic muscle cells from Gallus gallus. Our results show an increase in acidic compartment size and area, as well as changes in their positioning during the initial steps of myogenesis. The inhibition of lysosomal function by either the chloroquine Lys05 or the downregulation of LAMP-2 with siRNA impaired chick myogenesis, by inhibiting myoblast fusion. Two activators of the Wnt/beta-catenin pathway, BIO and Wnt3a, were able to rescue the inhibitory effects of Lys05 in myogenesis. These results suggest a new role for the Wnt/beta-catenin pathway in the regulation of acidic compartment size, positioning, and function in muscle cells.

scholarly journals Dissecting the regulation and function of ATP at the single-cell level

PLoS Biology ◽  
2018 ◽  
Vol 16 (12) ◽  
pp. e3000095 ◽  
Author(s):  
Jianhan Zhang ◽  
Xu Han ◽  
Yihan Lin
Keyword(s):  
Single Cell ◽  
Single Cell Level ◽  
Cell Level ◽  
And Function
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