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Cellular and Molecular Life Sciences :... Aug 2017Calpains are Ca-dependent intracellular proteases that play central roles in the post-translational processing of functional proteins. In mammals, calpain proteolytic... (Review)
Review
Calpains are Ca-dependent intracellular proteases that play central roles in the post-translational processing of functional proteins. In mammals, calpain proteolytic systems comprise the endogenous inhibitor calpastatin as well as 15 homologues of the catalytic subunits and two homologues of the regulatory subunits. Recent pharmacological and gene targeting studies in experimental animal models have revealed the contribution of conventional calpains, which consist of the calpain-1 and -2 isozymes, to atherosclerotic diseases. During atherogenesis, conventional calpains facilitate the CD36-dependent uptake of oxidized low-density lipoprotein (LDL), and block cholesterol efflux through ATP-binding cassette transporters in lesional macrophages, allowing the expansion of lipid-enriched atherosclerotic plaques. In addition, calpain-6, an unconventional non-proteolytic calpain, in macrophages reportedly potentiates pinocytotic uptake of native LDL, and attenuates the efferocytic clearance of apoptotic and necrotic cell corpses from the lesions. Herein, we discuss the recent progress that has been made in our understanding of how calpain contributes to atherosclerosis, in particular focusing on macrophage cholesterol handling.
Topics: ATP-Binding Cassette Transporters; Animals; Atherosclerosis; CD36 Antigens; Calpain; Cholesterol; Humans; Lipoproteins, LDL; Macrophages; Phagocytosis; Pinocytosis; Plaque, Atherosclerotic; Proteolysis; Receptors, Scavenger
PubMed: 28432377
DOI: 10.1007/s00018-017-2528-7 -
Proceedings of the National Academy of... Dec 2021In fast-moving cells such as amoeba and immune cells, dendritic actin filaments are spatiotemporally regulated to shape large-scale plasma membrane protrusions. Despite...
In fast-moving cells such as amoeba and immune cells, dendritic actin filaments are spatiotemporally regulated to shape large-scale plasma membrane protrusions. Despite their importance in migration, as well as in particle and liquid ingestion, how their dynamics are affected by micrometer-scale features of the contact surface is still poorly understood. Here, through quantitative image analysis of on microfabricated surfaces, we show that there is a distinct mode of topographical guidance directed by the macropinocytic membrane cup. Unlike other topographical guidance known to date that depends on nanometer-scale curvature sensing protein or stress fibers, the macropinocytic membrane cup is driven by the Ras/PI3K/F-actin signaling patch and its dependency on the micrometer-scale topographical features, namely PI3K/F-actin-independent accumulation of Ras-GTP at the convex curved surface, PI3K-dependent patch propagation along the convex edge, and its actomyosin-dependent constriction at the concave edge. Mathematical model simulations demonstrate that the topographically dependent initiation, in combination with the mutually defining patch patterning and the membrane deformation, gives rise to the topographical guidance. Our results suggest that the macropinocytic cup is a self-enclosing structure that can support liquid ingestion by default; however, in the presence of structured surfaces, it is directed to faithfully trace bent and bifurcating ridges for particle ingestion and cell guidance.
Topics: Cell Membrane; Chemotaxis; Computer Simulation; Dictyostelium; Models, Biological; Movement; Phosphatidylinositol 3-Kinases; Pinocytosis; Signal Transduction
PubMed: 34876521
DOI: 10.1073/pnas.2110281118 -
Frontiers in Immunology 2021
Topics: Neoplasms; Phagocytes; Phagocytosis; Pinocytosis; Receptors, IgG
PubMed: 34630442
DOI: 10.3389/fimmu.2021.772256 -
International Journal of Molecular... Jul 2020Mitochondrial transfer has been recognized to play a role in a variety of processes, ranging from fertilization to cancer and neurodegenerative diseases as well as... (Review)
Review
Mitochondrial transfer has been recognized to play a role in a variety of processes, ranging from fertilization to cancer and neurodegenerative diseases as well as mammalian horizontal gene transfer. It is achieved through either exogeneous or intercellular mitochondrial transfer. From the viewpoint of evolution, exogeneous mitochondrial transfer is quite akin to the initial process of symbiosis between α-protobacterium and archaea, although the progeny have developed more sophisticated machinery to engulf environmental materials, including nutrients, bacteria, and viruses. A molecular-based knowledge of endocytosis, including macropinocytosis and endosomal escape involving bacteria and viruses, could provide mechanistic insights into exogeneous mitochondrial transfer. We focus on exogeneous mitochondrial transfer in this review to facilitate the clinical development of the use of isolated mitochondria to treat various pathological conditions. Several kinds of novel procedures to enhance exogeneous mitochondrial transfer have been developed and are summarized in this review.
Topics: Animals; DNA, Mitochondrial; Endocytosis; Endosomes; Gene Transfer, Horizontal; Humans; Mitochondria; Pinocytosis; Symbiosis
PubMed: 32679802
DOI: 10.3390/ijms21144995 -
Philosophical Transactions of the Royal... Feb 2019
Topics: Animals; Humans; Macrophages; Pinocytosis
PubMed: 30967000
DOI: 10.1098/rstb.2018.0146 -
ELife Feb 2020Transport of fluids, molecules, nutrients or nanoparticles through coral tissues are poorly documented. Here, we followed the flow of various tracers from the external...
Transport of fluids, molecules, nutrients or nanoparticles through coral tissues are poorly documented. Here, we followed the flow of various tracers from the external seawater to within the cells of all tissues in living animals. After entering the general coelenteric cavity, we show that nanoparticles disperse throughout the tissues via the paracellular pathway. Then, the ubiquitous entry gate to within the cells' cytoplasm is macropinocytosis. Most cells form large vesicles of 350-600 nm in diameter at their apical side, continuously internalizing their surrounding medium. Macropinocytosis was confirmed using specific inhibitors of PI3K and actin polymerization. Nanoparticle internalization dynamics is size dependent and differs between tissues. Furthermore, we reveal that macropinocytosis is likely a major endocytic pathway in other anthozoan species. The fact that nearly all cells of an animal are continuously soaking in the environment challenges many aspects of the classical physiology viewpoints acquired from the study of bilaterians.
Topics: Actins; Animals; Anthozoa; Cytoplasm; Dextrans; Diffusion; Models, Biological; Nanoparticles; Pinocytosis
PubMed: 32039759
DOI: 10.7554/eLife.50022 -
Cancer Discovery Jul 2021Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an...
Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer-associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs-it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging. SIGNIFICANCE: Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth..
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Humans; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms; Pinocytosis; Rho Guanine Nucleotide Exchange Factors; Signal Transduction; Stromal Cells; Tumor Microenvironment
PubMed: 33653692
DOI: 10.1158/2159-8290.CD-20-0119 -
Placenta Jul 2022Prolonged pregnancy describes a pregnancy that progresses beyond 42 weeks' gestation (294 days). In humans, prolonged pregnancy is associated with increasing perinatal... (Review)
Review
Prolonged pregnancy describes a pregnancy that progresses beyond 42 weeks' gestation (294 days). In humans, prolonged pregnancy is associated with increasing perinatal mortality, neonatal compromise and birth by Caesarean section. The underpinning reasons behind these increased risks are unknown; one potential explanation is reduced placental function due to ageing processes. This review describes the structural and functional changes seen in prolonged pregnancy in humans and in animal models. Prolonged pregnancies are associated with reduced placental growth, leading to an increase in fetal to placental weight ratio. Microscopic changes include aggregation of syncytiotrophoblast nuclei, reduced villous vascularity with a concomitant impairment of trophoblast transport processes (reduced pinocytosis); this is associated with increased evidence of oxidative stress, with downstream consequences including cellular senescence, autophagy and apoptosis; importantly many of these changes are similar to fetal growth restriction and pre-eclampsia. Thus, we argue that these observations provide evidence of ageing within the placenta, which may initially be adaptive but can become pathological leading to a reduction in placental function. This provides a biological basis for the increased risk of adverse outcomes observed in prolonged pregnancies. Greater insight into the effects and risks of placental ageing may be useful to guide clinicians on the management of prolonged pregnancies.
Topics: Animals; Cesarean Section; Female; Fetal Growth Retardation; Humans; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Prolonged
PubMed: 35058067
DOI: 10.1016/j.placenta.2022.01.009 -
Cell and Tissue Research Sep 2019The uptake of macromolecules and larger energy-rich particles into the cell is known as phagocytosis. Phagocytosed material is enzymatically degraded in membrane-bound... (Review)
Review
The uptake of macromolecules and larger energy-rich particles into the cell is known as phagocytosis. Phagocytosed material is enzymatically degraded in membrane-bound vesicles of the endosome/lysosome system (intracellular digestion). Whereas most, if not all, cells of the animal body are equipped with the molecular apparatus for phagocytosis and intracellular digestion, a few cell types are specialized for a highly efficient mode of phagocytosis. These are the ("professional") macrophages, motile cells that seek out and eliminate pathogenic invaders or damaged cells. Macrophages form the backbone of the innate immune system. Developmentally, they derive from specialized compartments within the embryonic mesoderm and early vasculature as part of the process of hematopoiesis. Intensive research has revealed in detail molecular and cellular mechanisms of phagocytosis and intracellular digestion in macrophages. In contrast, little is known about a second type of cell that is "professionally" involved in phagocytosis, namely the "enteric phagocyte." Next to secretory (zymogenic) cells, enteric phagocytes form one of the two major cell types of the intestine of most invertebrate animals. Unlike vertebrates, these invertebrates only partially digest food material in the intestinal lumen. The resulting food particles are absorbed by phagocytosis or pinocytosis and digested intracellularly. In this review, we provide a brief overview of the enteric phagocytes described electron microscopically for diverse invertebrate clades, to then to compare these cells with the "canonical" phagocyte ultrastructure established for macrophages. In addition, we will review observations and speculations associated with the hypothesis that macrophages are evolutionarily derived from enteric phagocytes. This idea was already proposed in the late nineteenth century by Elias Metschnikoff who pioneered the research of phagocytosis for both macrophages and enteric phagocytes. We presume that modern approaches to better understand phagocytosis will be helped by considering the deep evolutionary relationship between the two cell types.
Topics: Animals; Biological Evolution; Macrophages; Phagocytosis
PubMed: 31485720
DOI: 10.1007/s00441-019-03096-6 -
Advanced Drug Delivery Reviews Feb 2017In vivo screening of phage libraries in tumor-bearing mice has been used to identify peptides that direct phage homing to a tumor. The power of in vivo phage screening... (Review)
Review
In vivo screening of phage libraries in tumor-bearing mice has been used to identify peptides that direct phage homing to a tumor. The power of in vivo phage screening is illustrated by the recent discovery of peptides with unique tumor-penetrating properties. These peptides activate an endocytic transport pathway related to but distinct from macropinocytosis. They do so through a complex process that involves binding to a primary, tumor-specific receptor, followed by a proteolytic cleavage, and binding to a second receptor. The second receptor, neuropilin-1 (or neuropilin-2) activates the transport pathway. This trans-tissue pathway, dubbed the C-end Rule (CendR) pathway, mediates the extravasation transport through extravascular tumor tissue of payloads ranging from small molecule drugs to nanoparticles. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. Targeted delivery with tumor-penetrating peptides has been shown to specifically increase the accumulation of drugs, antibodies and nanotherapeutics in experimental tumors in vivo, and in human tumors ex vivo. Remarkably the payload does not have to be coupled to the peptide; the peptide activates a bulk transport system that sweeps along a drug present in the blood. Treatment studies in mice have shown improved anti-tumor efficacy and less damage to normal tissues with drugs ranging from traditional chemotherapeutics to antibodies, and to nanoparticle drugs.
Topics: Animals; Cell Line, Tumor; Cell-Penetrating Peptides; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Neuropilin-1; Neuropilin-2; Peptide Library; Peptides; Pinocytosis
PubMed: 27040947
DOI: 10.1016/j.addr.2016.03.008