Design

Journal of BioChemistry – Cover Design

Posted by on Apr 29, 2012 in Designs, Highlighted Gallery, Publications, Recent Works | 0 comments

Journal of BioChemistry – Cover Design

On The Cover: Artistic rendition of Golgi production of branched N-glycans on surface glycoproteins (right side, artistic rendition), leading to enhanced binding of extracellular galectin-3 (artistically modified from Protein Data Bank entry 1a3k (Seetharaman, J., Kanigsberg, A., Slaaby, R., Leffler, H., Barondes, S. H., and Rini, J. R. (1998) J. Biol. Chem. 273, 13047–13052)) and in turn preventing loss of surface glycoproteins to endocytosis (left side, artistic rendition). In T cells, growth signaling differentially regulates multiple Golgi enzymes (Mgat1, Mgat2, Mgat5, α-mannosidase II/IIx, and α-mannosidase Ia,b,c) and hexosamine pathway production of UDP-GlcNAc to promote N-glycan branching, CTLA-4 surface retention, and T cell growth arrest. For details see the article by Chen et al., pages 32454–32461. (more…)

Nature Communications Journal Illustration

Posted by on Apr 28, 2012 in Designs, Highlighted Gallery | 0 comments

Nature Communications Journal Illustration
Environmental and genetic interaction converges on the Golgi N-glycan branching enzyme Mgat1 and N-glycosylation of CTLA-4 in T cell blasts. Both down- or upregulation of Mgat1 activity decrease branching by limiting N-glycan or UDP-GlcNAc substrate to downstream enzymes, respectively. (1) Soluble receptors associated with the IL2RA*T (rs2104286) and IL7RA*C (rs6897932) MS risk alleles antagonize IL-2 and IL-7 signalling, leading to (2) downregulation of Mgat1, decreased branching and CTLA-4 surface levels and increased MS risk. (3) Vitamin D3 signalling counteracts this by enhancing Mgat1, leading to increased branching, CTLA-4 surface expression and decreased MS risk. (4) The MGAT1 IVAVT–T haplotype (rs7726005, rs2070924, rs2070925) increases Mgat1, which decreases branching, CTLA-4 surface levels and increases MS risk conditional on (5) metabolic production of UDP-GlcNAc. (6) Combining genetic upregulation of Mgat1 by the MGAT1 IVAVT–T haplotype with genetic downregulation of Mgat1 by the IL2RA*T and IL7RA*C MS risk alleles optimizes Mgat1 activity, thereby enhancing branching, CTLA-4 surface expression and mitigating MS risk. The CTLA-4 Thr17Ala (rs231775) variant modifies these interactions by controlling the number of N-glycans attached to CTLA-4, with the Thr17 allele doubling N-glycan number to promote CTLA-4 surface retention and reduce MS risk when combined with MGAT1 IVAVT–T, IL2RA*TT and IL7RA*CC.

Immunological Reviews – Figure 2

Posted by on Apr 20, 2012 in Designs, Highlighted Gallery, Publications, Recent Work EXCLUDED | 0 comments

Immunological Reviews – Figure 2

Fig. 2 – Regulation of basal TCR signaling by the galectin-glycoprotein lattice.

Galectin binding to N-glycans attached to the TCR complex (which is depicted as a single ribbon) inhibits basal signaling via Lck by actively blocking spontaneous TCR oligomerization and subsequent recruitment of CD4-Lck, Nck, WASp, and SLP-76 to TCR, F-actin reorganization and transfer of the complex to GM1 enriched membrane microdomains (GEMs) (LEFT). Concurrently, galectin binding to N-glycans attached to the tyrosine phosphatase CD45 counteracts F-actin, maintaining CD45 in GEMs, dephosphorylating Tyr394 and inactivating Lck (RIGHT). CD45 is tethered to F-actin via the ankyrin-spectrin scaffold.

Immunological Reviews – Figure 5

Posted by on Apr 20, 2012 in Designs, Highlighted Gallery, Publications, Recent Work EXCLUDED | 0 comments

Immunological Reviews – Figure 5

Fig. 5 – Metabolism controls cell growth by regulating the galectin-glycoprotein lattice.

The nutrient environment and/or growth signaling by TCR influences UDP-GlcNAc production by the hexosamine pathway, which in turn regulates N-glycan branching in the Golgi to control galectin-glycoprotein lattice strength. Subsequent changes in cell surface receptor membrane localization and concentration results in differential responses to external factors (eg. Growth factors, peptide-MHC) that signal to the nucleus.

Immunological Reviews – Figure 4

Posted by on Apr 20, 2012 in Designs, Highlighted Gallery, Publications, Recent Work EXCLUDED | 0 comments

Immunological Reviews – Figure 4

Fig. 4. Regulation of CTLA-4 mediated growth arrest by the galectin-glycoprotein lattice.

Galectin binding to N-glycans attached to CTLA-4 enhances surface retention by opposing endocytic loss, resulting in sustained and increased arrest signaling. CTLA-4 has only two N-glycan sites and undergoes rapid degradation due to high constitutive endocytosis rates via AP-2-mediated targeting into clathrin-coated pits. TCR signaling increases metabolic flux to N-glycan branching, promoting incorporation of CTLA-4 into the galectin-glycoprotein lattice to sustain surface retention and augment growth arrest.

Immunological Reviews – Figure 3

Posted by on Apr 20, 2012 in Designs, Highlighted Gallery, Publications, Recent Work EXCLUDED | 0 comments

Immunological Reviews – Figure 3

Fig. 3 – Regulation of T cell activation thresholds by the galectin-glycoprotein lattice

Galectin binding to N-glycans attached to the TCR complex (which is depicted as a single ribbon) restricts clustering of TCR at the immune synapse in response to agonist (LEFT). Peptide-MHC overcomes galectin-TCR interactions to induce clustering, F-actin transfer to the immune synapse and signaling. Concurrently, galectin targets CD45 to the immune synapse, suppressing Lck activation and TCR signaling. Differential partitioning of TCR/CD4-Lck versus CD45 in the early immune synapse is in part predetermined by galectin-glycoprotein lattice control of GEM structure prior to encounter with TCR ligand.