Galectin-9 binds to O-glycans on protein disulfide isomerase

Schaefer, Katrin; Webb, Nicholas E.; Pang, Mabel; Hernandez-Davies, Jenny E.; Lee, Katharine P; Gonzalez, Pascual; Douglass, Martin V.; Lee, Benhur; Baum, Linda G.

doi:10.1093/glycob/cwx065

Cited by 32 publications

(28 citation statements)

References 76 publications

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“…It renders CD4 + T cells less susceptible to HIV infection via induction of the host restriction factor cyclin-dependent kinase inhibitor 1 (p 21) (42). It can also increase HIV entry by inducing the CD4 + T cell-surface concentration of protein disulfide isomerase (PDI) (43). We have previously shown that the endogenous levels of Gal-9 are induced after HIV infection and that these levels do not return to normal levels after ART suppression (20).…”

Section: Discussionmentioning

confidence: 99%

Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling

et al. 2019

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Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. However, the signaling mechanisms underlying Gal-9-mediated viral transcription remain unclear. Given that galectins are known to modulate T cell receptor (TCR)-signaling, we hypothesized that Gal-9 modulates HIV transcriptional activity, at least in part, through inducing TCR signaling pathways. Gal-9 induced T cell receptor ζ chain (CD3ζ) phosphorylation (11.2 to 32.1%; P = 0.008) in the J-Lat HIV latency model. Lck inhibition reduced Gal-9-mediated viral reactivation in the J-Lat HIV latency model (16.8–0.9%; P < 0.0001) and reduced both Gal-9-mediated CD4 + T cell activation (10.3 to 1.65% CD69 and CD25 co-expression; P = 0.0006), and IL-2/TNFα secretion ( P < 0.004) in primary CD4 + T cells from HIV-infected individuals on suppressive ART. Using phospho-kinase antibody arrays, we found that Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules ERK1/2 (26.7-fold) and CREB (6.6-fold). ERK and CREB inhibitors significantly reduced Gal-9-mediated viral reactivation (16.8 to 2.6 or 12.6%, respectively; P < 0.0007). Given that the immunosuppressive rapamycin uncouples HIV latency reversal from cytokine-associated toxicity, we also investigated whether rapamycin could uncouple Gal-9-mediated latency reactivation from its concurrent pro-inflammatory cytokine production. Rapamycin reduced Gal-9-mediated secretion of IL-2 (4.4-fold, P = 0.001) and TNF (4-fold, P = 0.02) without impacting viral reactivation (16.8% compared to 16.1%; P = 0.2). In conclusion, Gal-9 modulates HIV transcription by activating the TCR-downstream ERK and CREB signaling pathways in an Lck-dependent manner. Our findings could have implications for understanding the role of endogenous galectin interactions in modulating TCR signaling and maintaining chronic immune activation during ART-suppressed HIV infection. In addition, uncoupling Gal-9-mediated viral reactivation from undesirable pro-inflammatory effects, using rapamycin, may increase the potential utility of recombinant Gal-9 within the reversal of HIV latency eradication framework.

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Section: Discussionmentioning

confidence: 99%

Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling

et al. 2019

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“…Gal-9 also binds to protein disulfide isomerase (PDI), a cell surface enzyme. This binding increases PDI retention on the surface of CD4 + Th2 cells and alters the redox status of the plasma membrane; consequently, Gal-9 increases cell migration through the extracellular matrix via β 3 integrin [ 33 , 34 ].…”

Section: Galectin-9 Molecular and Cellular Biologymentioning

confidence: 99%

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

et al. 2021

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Galectin-9 (Gal-9) is a β-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases.

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“…Our finding that somite cell surface PDI (csPDI) binds PNA, and is lactose-elutable from immobilized PNA, indicates that this form of PDI is O-glycosylated. This is supported by the observation that csPDI expressed by Jurkat T cells, immortalized from human T cell leukaemia, also possesses PNA-binding O-glycans, the elongation of which can be blocked experimentally 21,22 . In addition, using a sensitive fluorescent reductase assay 23 we found that commercially purified (bovine liver) PDI does not bind to PNA-agarose, indicating that somite csPDI has an affinity for PNA based on its glycosylation state ( Figure 1-figure supplement 1b ).…”

Section: Resultsmentioning

confidence: 79%

Regulation of nerve growth and patterning by cell surface protein disulphide isomerase

Cook

Sousa

Schaeffer

et al. 2019

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30Contact repulsion of growing axons is an essential mechanism for spinal nerve 31 patterning. In birds and mammals the embryonic somites generate a linear series of 32 impenetrable barriers, forcing axon growth cones to traverse one half of each somite 33 as they extend towards their body targets. This study shows that protein disulphide 34 isomerase provides a key component of these barriers, mediating contact repulsion 35 at the cell surface in half-somites. Repulsion is reduced both in vivo and in vitro by a 36 range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric 37 oxide/S-nitrosylation-dependent signal transduction pathway that regulates the 38 growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar 39 activity, and the enzyme is expressed at the surface of cultured human astrocytic 40 cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to 41 counteract and regulate aberrant nerve terminal growth. 43Introduction 44 Peripheral spinal nerves have a striking anatomical periodicity, or segmentation, 45 that reflects their necessary isolation from the segments of developing bone that will 46 form the vertebral column. This study sets out to identify the molecular basis of this 47 patterning. We find a critical role for the enzyme protein disulfide isomerase in 48 separating outgrowing axons from the somite cells that generate the vertebrae, and 49 provide evidence regarding the underlying mechanism. 50In avian and mammalian embryos, both outgrowing motor and sensory axons, and 51 migrating neural crest cells, encounter the periodic somites that flank both sides of 52 the neural tube (future spinal cord). Here they traverse preferentially the anterior (A, 53 rostral/cranial) -rather than posterior (P, caudal) -halves of each successive 54 2 somite 1-4 . For neural crest cells this preference has been shown to depend on 55 repulsive signalling in the P-half-somite by members of the Semaphorin/Neuropilin-56 and Ephrin/Eph protein families [5][6][7][8][9] . However the basis of axonal segmental 57 patterning has remained elusive. 58We previously identified contact repulsion as the main cellular mechanism 59 generating axonal patterning 10,11 . Sequential repulsion of outgrowing motor and 60 sensory axons in successive P-half-sclerotomes (future vertebrae) forces axons to 61 traverse the anterior (A/cranial) halves. We showed that extracts of chick embryo 62 somites cause growth cone collapse of both motor and sensory axons in vitro 10 , a 63 phenomenon that is widely used as a method for identifying molecules that regulate 64 growth cone motility 12,13 . Additionally we found that the lectins peanut agglutinin 65 (PNA) and jacalin bind selectively to the surface of P-half-sclerotome cells rather 66 than A-half-sclerotome cells 10,14 . Immobilized PNA can be used to deplete collapse 67 activity, and activity is recovered by lactose elution. Biochemical purification led to 68 the identification of two PNA-binding glycoprote...

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Galectin-9 binds to O-glycans on protein disulfide isomerase

Cited by 32 publications

References 76 publications

Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling

Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

Regulation of nerve growth and patterning by cell surface protein disulphide isomerase

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