Dataset Information

Variability in the Glycosylation Patterns of gp120 Proteins from Different Human Immunodeficiency Virus Type 1 Isolates Expressed in Different Host Cells

ABSTRACT: The mature HIV-1 envelope (Env) glycoprotein is composed of gp120, the exterior subunit, and gp41, the transmembrane subunit assembled as trimer by noncovalent interaction. There is a great body of literature to prove that gp120 binds to CD4 first, then to the co-receptor. We have recently demonstrated that gp120 cannot bind to the co-receptor without first interacting with CD4. Previous studies provided different glycomic maps for the HIV-1 gp120. Here, we build on previous work to report that the use of LC-MS/MS, in conjunction with hydrophilic interaction liquid chromatography (HILIC) enrichment to glycosylation sites, is associated with the assorted neutralizing or binding events of glycosylation targeted antibodies from different clades or strains. In this study, the microheterogeneity of the glycosylation from 4 different clades of gp120s is deeply investigated. Aberrant glycosylation patterns were detected on gp120 originated from different clades, viral sequences and host cells. The results of this study may help provide better understanding of the mechanism of how the glycans participate in antibody neutralizing process that target glycosylation sites.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Human Immunodeficiency Virus 1

TISSUE(S): Cell Culture

SUBMITTER: Yifan Huang

LAB HEAD: Yehia Mechref

PROVIDER: PXD027353 | Pride | 2021-11-01

REPOSITORIES: Pride

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			Action	DRS
	GP120-1_062513sample_HILIC_120313_01.raw	Raw
	GP120-1_PNGaseF_091113_01.raw	Raw
	GP120-1_TrypsinGluC_HILIC_120413_01.raw	Raw
	GP120-4_062513sample_HILIC_120313_01.raw	Raw
	GP120-4_PNGaseF_091113_01.raw	Raw

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Project description:Phosphomannomutase 2 (PMM2) converts mannose-6-phospahate to mannose-1-phosphate; the substrate for GDP-mannose, a building block of the glycosylation biosynthetic pathway. Pathogenic variants in the PMM2 gene have been shown to be associated with protein hypoglycosylation causing PMM2-congenital disorder of glycosylation (PMM2-CDG). While mannose supplementation improves glycosylation in vitro, but not in vivo, we hypothesized that liposomal delivery of mannose-1-phosphate could increase the stability and delivery of the activated sugar to enter the targeted compartments of cells. Thus, we studied the effect of liposome-encapsulated mannose-1-P (GLM101) on global protein glycosylation and on the cellular proteome in skin fibroblasts from individuals with PMM2-CDG, as well as in individuals with two N-glycosylation defects early in the pathway, namely ALG2-CDG and ALG11-CDG. We leveraged multiplexed proteomics and N-glycoproteomics in fibroblasts derived from different individuals with various pathogenic variants in PMM2, ALG2 and ALG11 genes. Proteomics data revealed a moderate but significant change in the abundance of some of the proteins in all CDG fibroblasts upon GLM101 treatment. On the other hand, N-glycoproteomics revealed the GLM101 treatment enhanced the expression levels of several high-mannose and complex/hybrid glycopeptides from numerous cellular proteins in individuals with defects in PMM2 and ALG2 genes. Both PMM2-CDG and ALG2-CDG exhibited several-fold increase in glycopeptides bearing Man6 and higher glycans and a decrease in Man5 and smaller glycan moieties, suggesting that GLM101 helps in the formation of mature glycoforms. These changes in protein glycosylation were observed in all individuals irrespective of their genetic variants. ALG11-CDG fibroblasts also showed increase in high mannose glycopeptides upon treatment; however, the improvement was not as dramatic as the other two CDG. Overall, our findings suggest that treatment with GLM101 overcomes the genetic block in the glycosylation pathway and can be used as a potential therapy for CDG with enzymatic defects in early steps in protein N-glycosylation.

Dataset Information

Variability in the Glycosylation Patterns of gp120 Proteins from Different Human Immunodeficiency Virus Type 1 Isolates Expressed in Different Host Cells

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