Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes

Weng, I-Chun; Chen, Hung-Lin; Lo, Tzu-Han; Lin, Wei-Yang; Hsu, Daniel K.; Liu, Fu‐Tong

doi:10.1093/glycob/cwy017

Cited by 54 publications

(53 citation statements)

References 62 publications

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“…Our current study focuses on interpreting the extracellular function of galectin-3 but it seems probable that the NTD's ability to phase separate may also contribute to many of its intracellular functions, such as sensing danger by detecting unusual glycan exposure on damaged phagosomes 76 or by regulating RNA splicing 77 as do many RNA binding proteins with a prion-like domain (e.g., FUS, TDP-43). Moreover, many of the mechanisms governing the behavior of galectin-3 are still puzzling.…”

Section: Discussionmentioning

confidence: 99%

Liquid-liquid phase separation and extracellular multivalent interactions in the tale of galectin-3

et al. 2020

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Liquid-liquid phase separation (LLPS) explains many intracellular activities, but its role in extracellular functions has not been studied to the same extent. Here we report how LLPS mediates the extracellular function of galectin-3, the only monomeric member of the galectin family. The mechanism through which galectin-3 agglutinates (acting as a "bridge" to aggregate glycosylated molecules) is largely unknown. Our data show that its N-terminal domain (NTD) undergoes LLPS driven by interactions between its aromatic residues (two tryptophans and 10 tyrosines). Our lipopolysaccharide (LPS) micelle model shows that the NTDs form multiple weak interactions to other galectin-3 and then aggregate LPS micelles. Aggregation is reversed when interactions between the LPS and the carbohydrate recognition domains are blocked by lactose. The proposed mechanism explains many of galectin-3's functions and suggests that the aromatic residues in the NTD are interesting drug design targets.

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Section: Discussionmentioning

confidence: 99%

Liquid-liquid phase separation and extracellular multivalent interactions in the tale of galectin-3

et al. 2020

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“…TRIM16 serves as another assembly hub to initiate autophagy by recruiting the core autophagic machinery (ATG16L1, ULK1, and Beclin-1) directly on damaged membranes [ 104 ]. Interestingly, the recruitment of Gal3 to the membrane damage side can also be pro-bacterial by impeding on the autophagic response [ 106 ]. Silencing of Gal3 during L. monocytogenes infection in murine macrophages increased LC3 recruitment to the vacuoles and reduced bacterial replication.…”

Section: Membrane Damage Recognition and Cell Responsementioning

confidence: 99%

“…Moreover, treatment of cells with sialidase (which removes sialic acid from glycans) increased Gal3 and decreased Gal8 on the damaged phagosomes. This change in Gal preference directly influenced the autophagic response [ 106 ], showing that cytosolic Gals can discriminate the origin of the damaged membrane and orchestrate an adapted cellular response. Deciphering the glycosylation pattern driving Gal specificity could thus be a valuable point for therapeutic intervention.…”

Section: Membrane Damage Recognition and Cell Responsementioning

confidence: 99%

“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective

Daussy

Wodrich

2020

Cells

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Cells are constantly challenged by pathogens (bacteria, virus, and fungi), and protein aggregates or chemicals, which can provoke membrane damage at the plasma membrane or within the endo-lysosomal compartments. Detection of endo-lysosomal rupture depends on a family of sugar-binding lectins, known as galectins, which sense the abnormal exposure of glycans to the cytoplasm upon membrane damage. Galectins in conjunction with other factors orchestrate specific membrane damage responses such as the recruitment of the endosomal sorting complex required for transport (ESCRT) machinery to either repair damaged membranes or the activation of autophagy to remove membrane remnants. If not controlled, membrane damage causes the release of harmful components including protons, reactive oxygen species, or cathepsins that will elicit inflammation. In this review, we provide an overview of current knowledge on membrane damage and cellular responses. In particular, we focus on the endo-lysosomal damage triggered by non-enveloped viruses (such as adenovirus) and discuss viral strategies to control the cellular membrane damage response. Finally, we debate the link between autophagy and inflammation in this context and discuss the possibility that virus induced autophagy upon entry limits inflammation.

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“…Galectins are a family of β-galactoside-binding cytosolic lectins that monitors endosomal and lysosomal integrity. These danger receptors can detect bacterial invasion by detecting unusual exposure of glycans to the cytosol and activate antibacterial autophagy [66][67][68]. Immunohistochemistry analysis of leprosy lesions revealed a higher expression of galectin-3 protein on lepromatous macrophages than tuberculoid cells.…”

Section: Leprae Causes Phagosome Maturation Arrest and Phagosomal Permentioning

confidence: 99%

“…The increased galectin-3 expression in lepromatous cells was associated with the reduction of dendritic cell differentiation and T-cell antigen presentation [69]. Interestingly, galectin-3 was associated with both bacterial control and survival, as well as autophagy activation and inhibition [66,68], whereas galectin-8 was related to antibacterial autophagy activation [67,68]. The underlying cellular mechanisms of target M. leprae as an autophagic cargo destination in human macrophages are still not fully understood; some of them displayed in Figure 3 are insights from M. tuberculosis infection model.…”

Section: Leprae Causes Phagosome Maturation Arrest and Phagosomal Permentioning

confidence: 99%

Macrophages in the Pathogenesis of Leprosy

Prata¹,

Barbosa²,

Silva³

et al. 2020

Macrophage Activation - Biology and Disease

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Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae. The disease may present different clinical forms depending on the immunological status of the host. M. leprae may infect macrophages and Schwann cells, and recent studies have demonstrated that macrophages are fundamental cells for determining the outcome of the disease. Skin lesions from patients with the paucibacillary form of the disease present a predominance of macrophages with a pro-inflammatory phenotype (M1), whereas skin lesions of multibacillary patients present a predominance of anti-inflammatory macrophages (M2). More recently, it was shown that autophagy is responsible for the control of bacillary load in paucibacillary macrophages and that the blockade of autophagy is involved in the onset of acute inflammatory reactional episodes in multibacillary cells. So, strategies that aim to induce autophagy in infected macrophages are promising not only to improve the efficacy of multidrug therapy (MDT) but also to avoid the occurrence of reactional episodes that are responsible for the disabilities observed in leprosy patients.2 production of nitric oxide, thus causing peripheral nerve damage characteristic of patients with leprosy [10]. Other studies have shown the ability of M. leprae to induce the production of oxidative mediators and their products, peroxynitrite and nitrotyrosine [11][12][13][14].Studies have demonstrated the ability of M. leprae to interact with a range of scavenger receptors of macrophages culminating in a tolerogenic response profile. The scavenger receptors are membrane receptors whose main function is the removal of molecules and cellular debris from the body, binding through a variety of polyanions, leading to phagocytosis of the target, being found in several cell types such as macrophages [15]. The ability of M. leprae to interact with the CD163 receptor, a scavenger receptor, which, during this interaction, can act as a co-receptor for M. leprae entry in macrophages, has been described [16]. It is known that activation of this receptor is related to the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), leading to the synthesis and increase of the activity of the enzyme heme oxygenase-1 (HO-1), which, through anti-inflammatory and antioxidant pathways, releases interleukin (IL)-10 and generates carbon monoxide, contributing to the polarization of these cells [17][18][19]. Bonilla and colleagues [20] demonstrated that autophagy, a mechanism of metabolic control, regulates the expression of scavenger receptors macrophage receptor with collagenous structure (MARCO) and scavenger receptor type A (SRA-I) that increase phagocytosis and NRF2 activity during Bacillus Calmette-Guérin (BCG) or M. tuberculosis (H37Rv) infection.M. leprae is able to induce macrophage SRA-I and CD36 expression [6] that contributes to the uptake of lipids, culminating in an increase in the uptake and accumulation of oxidized lipids within the macrophages, leading to a fo...

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Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes

Cited by 54 publications

References 62 publications

Liquid-liquid phase separation and extracellular multivalent interactions in the tale of galectin-3

Liquid-liquid phase separation and extracellular multivalent interactions in the tale of galectin-3

“Repair Me if You Can”: Membrane Damage, Response, and Control from the Viral Perspective

Macrophages in the Pathogenesis of Leprosy

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