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Open accessJournal ArticleDOI: 10.1186/S12929-021-00713-X

Intracellular galectins sense cytosolically exposed glycans as danger and mediate cellular responses.

04 Mar 2021-Journal of Biomedical Science (BioMed Central)-Vol. 28, Iss: 1, pp 16-16
Abstract: Galectins are animal lectins that recognize carbohydrates and play important roles in maintaining cellular homeostasis. Recent studies have indicated that under a variety of challenges, intracellular galectins bind to host glycans displayed on damaged endocytic vesicles and accumulate around these damaged organelles. Accumulated galectins then engage cellular proteins and subsequently control cellular responses, such as autophagy. In this review, we have summarized the stimuli that lead to the accumulation of galectins, the molecular mechanisms of galectin accumulation, and galectin-mediated cellular responses, and elaborate on the differential regulatory effects among galectins.

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Topics: Galectin (58%), Cellular homeostasis (57%), Endocytic vesicle (54%)

5 results found

Open accessJournal ArticleDOI: 10.3390/CANCERS13184529
Diego Jose Laderach1, Daniel Compagno1Institutions (1)
09 Sep 2021-Cancers
Abstract: Current data indicates that anti-tumor T cell-mediated immunity correlates with a better prognosis in cancer patients. However, it has widely been demonstrated that tumor cells negatively manage immune attack by activating several immune-suppressive mechanisms. It is, therefore, essential to fully understand how lymphocytes are activated in a tumor microenvironment and, above all, how to prevent these cells from becoming dysfunctional. Tumors produce galectins-1, -3, -7, -8, and -9 as one of the major molecular mechanisms to evade immune control of tumor development. These galectins impact different steps in the establishment of the anti-tumor immune responses. Here, we carry out a critical dissection on the mechanisms through which tumor-derived galectins can influence the production and the functionality of anti-tumor T lymphocytes. This knowledge may help us design more effective immunotherapies to treat human cancers.

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Topics: Tumor microenvironment (56%), Tumor-Derived (55%), Galectin (54%) ... show more

Open accessJournal ArticleDOI: 10.1016/J.IJPHARM.2021.121308
Abstract: The utilization of nanoparticles for the intracellular delivery of theranostic agents faces one substantial limitation. Sequestration in intracellular vesicles prevents them from reaching the desired location in the cytoplasm or nucleus to deliver their cargo. We investigated whether three different cell-penetrating peptides (CPPs), namely, octa-arginine R8, polyhistidine KH27K and histidine-rich LAH4, could promote cytosolic and/or nuclear transfer of unique model nanoparticles—pseudovirions derived from Murine polyomavirus. Two types of CPP-modified pseudovirions that carry the luciferase reporter gene were created: VirPorters-IN with CPPs genetically attached to the capsid interior and VirPorters-EX with CPPs noncovalently associated with the capsid exterior. We tested their transduction ability by luciferase assay and monitored their presence in subcellular fractions. Our results confirmed the overall effect of CPPs on the intracellular destination of the particles and suggested that KH27K has the potential to improve the cytosolic release of pseudovirions. None of the VirPorters caused endomembrane damage detectable by the Galectin-3 assay. Remarkably, a noncovalent modification was required to promote high transduction of the reporter gene and cytosolic delivery of pseudovirions mediated by LAH4. Together, CPPs in different arrangements have demonstrated their potential to improve pseudovirion invasion into cells, and these findings could be useful for the development of other nanoparticle-based delivery systems.

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Topics: Cell-penetrating peptide (58%), Pseudovirion (52%), Reporter gene (51%)

Open accessJournal ArticleDOI: 10.1002/CBIC.202100327
Hans-Joachim Gabius1, Mare Cudic2, Tammo Diercks, Herbert Kaltner1  +8 moreInstitutions (9)
22 Sep 2021-ChemBioChem
Abstract: A code is defined by the nature of the symbols, which are used to generate information-storing combinations (e. g. oligo- and polymers). Like nucleic acids and proteins, oligo- and polysaccharides are ubiquitous, and they are a biochemical platform for establishing molecular messages. Of note, the letters of the sugar code system (third alphabet of life) excel in coding capacity by making an unsurpassed versatility for isomer (code word) formation possible by variability in anomery and linkage position of the glycosidic bond, ring size and branching. The enzymatic machinery for glycan biosynthesis (writers) realizes this enormous potential for building a large vocabulary. It includes possibilities for dynamic editing/erasing as known from nucleic acids and proteins. Matching the glycome diversity, a large panel of sugar receptors (lectins) has developed based on more than a dozen folds. Lectins 'read' the glycan-encoded information. Hydrogen/coordination bonding and ionic pairing together with stacking and C-H/π-interactions as well as modes of spatial glycan presentation underlie the selectivity and specificity of glycan-lectin recognition. Modular design of lectins together with glycan display and the nature of the cognate glycoconjugate account for the large number of post-binding events. They give an entry to the glycan vocabulary its functional, often context-dependent meaning(s), hereby building the dictionary of the sugar code.

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Topics: Glycan (52%), Glycome (51%), Code word (50%)

Open accessPosted ContentDOI: 10.1101/2021.10.21.465009
Gina M. Borgo1, Thomas P. Burke1, Cuong J. Tran1, Nicholas T. N. Lo1  +2 moreInstitutions (1)
21 Oct 2021-bioRxiv
Abstract: Spotted fever group Rickettsia species are arthropod-borne obligate intracellular bacteria that can cause mild to severe human disease. These bacteria invade host cells, replicate in the cell cytosol, and then spread from cell to cell. To access the host cytosol and avoid detection by immune surveillance mechanisms, these pathogens must have evolved efficient ways to escape membrane-bound vacuoles. Although Rickettsia are predicted to express factors that disrupt host membranes, little is known about how and when these proteins function during infection. Here, we investigated the role of a Rickettsia patatin-like phospholipase A2 enzyme (Pat1) during host cell infection by characterizing a Rickettsia parkeri mutant with a transposon insertion in the pat1 gene. We show that Pat1 is important for infection in a mouse model and in host cells. We further show that Pat1 is critical for efficiently escaping from the single and double membrane-bound vacuoles into the host cytosol, and for avoiding host galectins that mark damaged membranes. In the host cytosol, Pat1 is important for avoiding host polyubiquitin, preventing recruitment of autophagy receptor p62, and promoting actin-based motility and cell-cell spread. Our results show that Pat1 plays critical roles in escaping host membranes and promoting cell-cell spread during R. parkeri infection and suggest diverse roles for patatin-like phospholipases in facilitating microbial infection. ImportanceSpotted fever group Rickettsia are bacteria that reside in ticks and can be transmitted to mammalian hosts, including humans. Severe disease is characterized by high fever, headache, and rash, and results in occasional mortality despite available treatment. Rickettsia interact with host cell membranes while invading cells, escaping into the cytosol, and evading cellular defenses. Bacterial phospholipase enzymes have been proposed as critical factors for targeting host cell membranes, however the specific roles of rickettsial phospholipases are not well defined. We investigated the contribution of one conserved patatin-like phospholipase, Pat1, in Rickettsia parkeri. We observed that Pat1 is important for virulence in an animal model. Moreover, Pat1 plays critical roles in host cells by facilitating access to the cell cytosol, inhibiting detection by host defense pathways, and promoting cell-cell spread. Our study indicates that Pat1 performs several critical functions, suggesting a broad role for phospholipases throughout the Rickettsia lifecycle.

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Journal ArticleDOI: 10.1080/15548627.2021.1969765
Alexander Gluschko1, Alina Farid1, Marc Herb1, Daniela Grumme1  +2 moreInstitutions (1)
05 Sep 2021-Autophagy
Abstract: Non-canonical autophagy pathways decorate single-membrane vesicles with Atg8-family proteins such as MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). Phagosomes containing the bacterial pathogen Listeria monocytogenes (L.m.) can be targeted by a non-canonical autophagy pathway called LC3-associated phagocytosis (LAP), which substantially contributes to the anti-listerial activity of macrophages and immunity. We here characterized a second non-canonical autophagy pathway targeting L.m.-containing phagosomes, which is induced by damage caused to the phagosomal membrane by the pore-forming toxin of L.m., listeriolysin O. This pore-forming toxin-induced non-canonical autophagy pathway (PINCA) was the only autophagic pathway evoked in tissue macrophages deficient for the NADPH oxidase CYBB/NOX2 that produces the reactive oxygen species (ROS) that are required for LAP induction. Similarly, also bone marrow-derived macrophages (BMDM) exclusively targeted L.m. by PINCA as they completely failed to induce LAP because of insufficient production of ROS through CYBB, in part, due to low expression of some CYBB complex subunits. Priming of BMDM with proinflammatory cytokines such as TNF and IFNG/IFNγ increased ROS production by CYBB and endowed them with the ability to target L.m. by LAP. Targeting of L.m. by LAP remained relatively rare, though, preventing LAP from substantially contributing to the anti-listerial activity of BMDM. Similar to LAP, the targeting of L.m.-containing phagosomes by PINCA promoted their fusion with lysosomes. Surprisingly, however, this did not substantially contribute to anti-listerial activity of BMDM. Thus, in contrast to LAP, PINCA does not have clear anti-listerial function suggesting that the two different non-canonical autophagy pathways targeting L.m. may have discrete functions.Abbreviations: actA/ActA: actin assembly-inducing protein A; ATG: autophagy-related; BMDM: Bone marrow-derived macrophages; CALCOCO2/NDP52: calcium-binding and coiled-coil domain-containing protein 2; CYBA/p22phox: cytochrome b-245 light chain; CYBB/NOX2: cytochrome b(558) subunit beta; E. coli: Escherichia coli; IFNG/IFNγ: interferon gamma; L.m.: Listeria monocytogenes; LAP: LC3-associated phagocytosis; LGALS: galectin; LLO: listeriolysin O; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NCF1/p47phox: neutrophil cytosol factor 1; NCF2/p67phox: neutrophil cytosol factor 2; NCF4/p67phox: neutrophil cytosol factor 4; Peritoneal macrophages: PM; PINCA: pore-forming toxin-induced non-canonical autophagy; plc/PLC: 1-phosphatidylinositol phosphodiesterase; PMA: phorbol 12-myristate 13-acetate; RB1CC1/FIP200: RB1-inducible coiled-coil protein 1; ROS: reactive oxygen species; S. aureus: Staphylococcus aureus; S. flexneri: Shigella flexneri; SQSTM1/p62: sequestosome 1; S. typhimurium: Salmonella typhimurium; T3SS: type III secretion system; TNF: tumor necrosis factor; ULK: unc-51 like autophagy activating kinase; PM: peritoneal macrophages; WT: wild type.

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Topics: Neutrophil cytosol factor 2 (59%), Sequestosome 1 (57%), CYBB (56%) ... show more

44 results found

Journal ArticleDOI: 10.1038/NRC1527
Fu-Tong Liu1, Gabriel A. Rabinovich2Institutions (2)
Abstract: Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?

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Topics: Galectin (61%), Galectin-3 (58%), Neoplastic transformation (56%) ... show more

1,229 Citations

Open accessJournal ArticleDOI: 10.1038/NATURE10744
16 Feb 2012-Nature
Abstract: Galectin 8, a cytosolic lectin, is shown to function as a danger receptor that detects damaged vesicles and protects cells from bacterial infection by inducing autophagy. The galectins are carbohydrate-binding proteins that have a range of functions inside and outside the cell. They accumulate in the cytosol, which is normally devoid of complex carbohydrates, making them prime candidates for danger and/or pattern-recognition receptors. Here galectin-8 is identified as a danger receptor that protects cells against bacterial infection. It binds to host glycans exposed on bacteria-containing vesicles and recruits the ubiquitin-binding autophagy receptor NDP52 to clear the cytosol of invading bacteria. Autophagy defends the mammalian cytosol against bacterial infection1,2,3. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating4,5,6,7,8,9. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.

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Topics: Galectin-8 (62%), Galectin (57%), Autophagy (53%) ... show more

727 Citations

Open accessJournal ArticleDOI: 10.1073/PNAS.93.13.6737
Ri Yao Yang1, Daniel K. Hsu1, Fu-Tong Liu1Institutions (1)
Abstract: Galectin-3 is a member (if a large family of beta-galactoside-binding animal lectins. It has been shown that the expression of galectin-3 is upregulated in proliferating cells, suggesting a possible role for this lectin in regulation of cell growth. Previously, we have shown that T cells infected with human T-cell leukemia virus type I express high levels of galectin-3, in contrast to uninfected cells, which do not express detectable amounts of this protein. In this study, we examined growth properties of human leukemia T cells transfected with galectin-3 cDNA, and thus constitutively overexpressing this lectin. Transfectants expressing galectin-3 displayed higher growth rates than control transfectants, which do not express this lectin. Furthermore, galectin-3 expression in these cells confers resistance to apoptosis induced by anti-Fas antibody and staurosporine. Galectin-3 was found to have significant sequence similarity with Bcl-2, a well-characterized suppressor of apoptosis. In particular, the lectin contains the NWGR motif that is highly conserved among members of the Bcl-2 family and shown to be critical for the apoptosis-suppressing activity. We further demonstrated that galectin-3 interacts with Bc1-2 in a lactose-inhibitable manner. We conclude that galectin-3 is a regulator of cell growth and apoptosis and it may function through a cell death inhibition pathway that involves Bcl-2.

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Topics: KLRB1 (62%), T cell (59%), Cell growth (56%) ... show more

713 Citations

Open accessJournal ArticleDOI: 10.1083/JCB.110.5.1681
Abstract: A soluble lactose-binding lectin with subunit Mr of 14,500 is believed to function by interacting with extracellular glycoconjugates, because it has been detected extracellularly by immunohistochemistry. This localization has been questioned, however, since the lectin lacks a secretion signal sequence, which challenges the contention that it is secreted. We have demonstrated externalization of this lectin from C2 mouse muscle cells by both immunoprecipitation of metabolically labeled protein and immunohistochemical localization. We further show that externalization of the lectin is a developmentally regulated process that accompanies myoblast differentiation and that the lectin codistributes with laminin in myotube extracellular matrix. Immunohistochemical localization during intermediate stages of externalization suggests that the lectin becomes concentrated in evaginations of plasma membrane, which pinch off to form labile lectin-rich extracellular vesicles. This suggests a possible mechanism for lectin export from the cytosol to the extracellular matrix.

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Topics: C-type lectin (74%), Mannan-binding lectin (70%), CD69 (66%) ... show more

460 Citations

Open accessJournal ArticleDOI: 10.1038/EMBOJ.2013.171
Ikuko Maejima1, Atsushi Takahashi1, Hiroko Omori1, Tomonori Kimura1  +7 moreInstitutions (2)
28 Aug 2013-The EMBO Journal
Abstract: Diverse causes, including pathogenic invasion or the uptake of mineral crystals such as silica and monosodium urate (MSU), threaten cells with lysosomal rupture, which can lead to oxidative stress, inflammation, and apoptosis or necrosis. Here, we demonstrate that lysosomes are selectively sequestered by autophagy, when damaged by MSU, silica, or the lysosomotropic reagent L-Leucyl-L-leucine methyl ester (LLOMe). Autophagic machinery is recruited only on damaged lysosomes, which are then engulfed by autophagosomes. In an autophagy-dependent manner, low pH and degradation capacity of damaged lysosomes are recovered. Under conditions of lysosomal damage, loss of autophagy causes inhibition of lysosomal biogenesis in vitro and deterioration of acute kidney injury in vivo. Thus, we propose that sequestration of damaged lysosomes by autophagy is indispensable for cellular and tissue homeostasis.

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Topics: Tissue homeostasis (53%), Autophagy (53%), Cellular homeostasis (53%) ... show more

309 Citations

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