Influence of Glycosylation Inhibition on the Binding of KIR3DL1 to HLA-B*57:01

Salzberger, Wilhelm; García-Beltrán, Wilfredo F.; Dugan, Haley L.; Gubbala, Supreetha; Simoneau, Camille R.; Gressens, Simon B.; Jost, Stéphanie; Altfeld, Marcus

doi:10.1371/journal.pone.0145324

Cited by 8 publications

(5 citation statements)

References 39 publications

(35 reference statements)

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“…These proteins have in common the complex post-translational modification that requires N-glycosylation for the correct localization (HFE), activation (TMPRSS6), and stabilization (TFR2) in the plasma membrane [44][45][46]. As proof of concept, we treated HuH7 cells with tunicamycin, an N-linked glycosylation inhibitor [47]. Treatment with increasing concentrations of tunicamycin demonstrated that the altered glycosylation led to a reduced expression of TFR2, HFE, and TMPRSS6 proteins.…”

Section: Discussionmentioning

confidence: 99%

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Rosato

Marra

D’Onofrio

et al. 2022

IJMS

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Biallelic pathogenic variants in the SEC23B gene cause congenital dyserythropoietic anemia type II (CDA II), a rare hereditary disorder hallmarked by ineffective erythropoiesis, hemolysis, erythroblast morphological abnormalities, and hypo-glycosylation of some red blood cell membrane proteins. Abnormalities in SEC23B, which encodes the homonymous cytoplasmic COPII (coat protein complex II) component, disturb the endoplasmic reticulum to Golgi trafficking and affect different glycosylation pathways. The most harmful complication of CDA II is the severe iron overload. Within our case series (28 CDA II patients), approximately 36% of them exhibit severe iron overload despite mild degree of anemia and slightly increased levels of ERFE (the only erythroid regulator of hepcidin suppression). Thus, we hypothesized a direct role of SEC23B loss-of-function in the pathomechanism of hepatic iron overload. We established a hepatic cell line, HuH7, stably silenced for SEC23B. In silenced cells, we observed significant alterations of the iron status, due to both the alteration in BMP/SMADs pathway effectors and a reduced capability to sense BMP6 stimulus. We demonstrated that the loss-of-function of SEC23B is responsible of the impairment in glycosylation of the membrane proteins involved in the activation of the BMP/SMADs pathway with subsequent hepcidin suppression. Most of these data were confirmed in another hepatic cell line, HepG2, stably silenced for SEC23B. Our findings suggested that the pathogenic mechanism of iron overload in CDA II is associated to both ineffective erythropoiesis and to a specific involvement of SEC23B pathogenic variants at hepatic level. Finally, we demonstrated the ability of SEC23B paralog, i.e., SEC23A, to rescue the hepcidin suppression, highlighting the functional overlap between the two SEC23 paralogs in human hepatic cells.

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Section: Discussionmentioning

confidence: 99%

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Rosato

Marra

D’Onofrio

et al. 2022

IJMS

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“…HLA-B*57:01 of the DBB and DEM cells displays a Bw4 motif, while B*07:02 of JY cells displays a Bw6 motif. HLA molecules harboring the Bw4 motif have been shown to elicit a stronger NK-cell response and the glycan attached to the HLA heavy chain is required for the NK-cell interaction . There may thus be a link between this Bw motif, the HLA glycosylation pattern, and the interaction with NK-cell KIR cells.…”

Section: Discussionmentioning

confidence: 99%

Allotype-Specific Glycosylation and Cellular Localization of Human Leukocyte Antigen Class I Proteins

Hoek

Demmers

et al. 2021

J. Proteome Res.

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Presentation of antigens by human leukocyte antigen (HLA) complexes at the cell surface is a key process in the immune response. The α-chain, containing the peptide-binding groove, is one of the most polymorphic proteins in the proteome. All HLA class I α-chains carry a conserved N-glycosylation site, but little is known about its nature and function. Here, we report an in-depth characterization of N-glycosylation features of HLA class I molecules. We observe that different HLA-A α-chains carry similar glycosylation, distinctly different from the HLA-B, HLA-C, and HLA-F α-chains. Although HLA-A displays the broadest variety of glycan characteristics, HLA-B α-chains carry mostly mature glycans, and HLA-C and HLA-F α-chains carry predominantly high-mannose glycans. We expected these glycosylation features to be directly linked to cellular localization of the HLA complexes. Indeed, analyzing HLA class I complexes from crude plasma and inner membrane-enriched fractions confirmed that most HLA-B complexes can be found at the plasma membrane, while most HLA-C and HLA-F molecules reside in the endoplasmic reticulum and Golgi membrane, and HLA-A molecules are more equally distributed over these cellular compartments. This allotype-specific cellular distribution of HLA molecules should be taken into account when analyzing peptide antigen presentation by immunopeptidomics.

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“…Cells were cultured for 1 week in custom-made Advanced RPMI-1640 (Life Technologies) with magnesium sulfate, zinc sulfate, and copper (II) sulfate replaced with their respective chloride salts, and supplemented with fetal calf serum (Sigma), GlutaMAX (Gibco), penicillin/streptomycin, and 150 mM sodium chlorate (Sigma) as described previously 75 . Cells were then used in the viral fusion assay as described.…”

Section: Methodsmentioning

confidence: 99%

A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

et al. 2016

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Host proteins are essential for entry and replication of HIV and provide important non-viral therapeutic targets. Large-scale RNAi-based screens have identified nearly a thousand candidate host factors, but with little agreement among studies and few validated factors. Here, we demonstrate that a genome-wide CRISPR-based screen identifies bona fide host factors in a physiologically relevant cell system. We identify five factors, including CD4 and CCR5, that are required for HIV infection yet dispensable for cellular proliferation and viability. TPST2 and SLC35B2 act in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating recognition by HIV envelope. ALCAM mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validate these pathways in primary human CD4+ T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest focusing on these pathways for therapeutic intervention.

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Influence of Glycosylation Inhibition on the Binding of KIR3DL1 to HLA-B*57:01

Cited by 8 publications

References 39 publications

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

SEC23B Loss-of-Function Suppresses Hepcidin Expression by Impairing Glycosylation Pathway in Human Hepatic Cells

Allotype-Specific Glycosylation and Cellular Localization of Human Leukocyte Antigen Class I Proteins

A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors

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