Faculty Opinions recommendation of The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer.

ABSTRACT Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.

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Glucose regulates expression of pro-inflammatory genes IL-1β and IL-12 through a mechanism involving hexosamine biosynthesis pathway dependent regulation of αEcatenin

Bioscience Reports ◽

10.1042/bsr20211066 ◽

2021 ◽

Author(s):

Waruni C Dissanayake ◽

Jin Kyo Oh ◽

Brie Sorrenson ◽

Peter R Shepherd

Keyword(s):

High Glucose ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Mrna Levels ◽

Biosynthesis Pathway ◽

Glucose Levels ◽

Raw264.7 Macrophages ◽

Hexosamine Biosynthesis ◽

Induced Changes ◽

Hexosamine Biosynthesis Pathway

High glucose levels are associated with changes in macrophage polarization and evidence indicates that the sustained or even short-term high glucose levels modulate inflammatory responses in macrophages. However, the mechanism by which macrophages can sense the changes in glucose levels are not clearly understood. We find that high glucose levels rapidly increase the α-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose induced increase of α-E catenin when hexosamine biosynthesis pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of hexosamine biosynthesis pathway in this process. Then, we investigated the potential role of α-E catenin in glucose induced macrophage polarization. We find that the reduction of α-E catenin level using siRNA attenuates the glucose induced changes of both IL-1β and IL-12 mRNA levels under LPS stimulated condition but does not affect TNF-α expression. Together this indicates that α-E catenin can sense the changes in glucose levels in macrophages via hexosamine biosynthesis pathway and also can modulate the glucose induced gene expression of inflammatory markers such as IL-1β and IL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.

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