Proteoglycan Metabolism
Virtually all animal cells carry proteoglycans on their plasma membrane and secrete them into the surrounding extracellular matrix. Proteoglycans consist of a protein core and one or more glycosaminoglycan chains, such as heparan sulfate (which is related in structure to the anticoagulant heparin) or chondroitin sulfate/dermatan sulfate. During their biosynthesis, a large family of enzymes install sulfate groups at various positions along the chains, creating binding sites for ligands, such as growth factors, proteases and their inhibitors, lipolytic enzymes and plasma apolipoproteins, and extracellular matrix proteins. The importance of these interactions is exemplified by the profound pathophysiological phenotypes in mice and humans bearing mutations in the core proteins or the biosynthetic enzymes responsible for assembly of the chains.
Ongoing projects include creation of conditional mutants in mice in order to study the function of heparan sulfate and chondroitin sulfate proteoglycans and their binding proteins. We are also interested in the process of assembly, in particular how cells regulate the formation of ligand binding sites in the chains. Towards this end, we have a genome wide CRISPR-Cas9 screenings underway to look for novel genes involved in assembly. These studies have led to the identification of unexpected factors that regulate the biosynthetic pathway, including transcription factors, chromatin remodeling genes, and components of several signaling pathways.
We are also interested in lysosomal catabolism of glycosaminoglycans and inherited diseases that alter their natural turnover. We work with TEGA Therapeutics towards the development of therapeutic forms of heparan sulfate and heparin and enzyme replacement therapies. We also work on the development of substrate reduction strategies in collaboration with Ionis Pharmaceuticals.
Relevant Papers
Poli, M., Anower-E-Khuda, F., Asperti, M., Ruzzenenti, P., Gryzik, M., Gordts, P.L.S.M., Arosio, P. and Esko, J.D. (2019) Hepatic heparan sulfate regulates hepcidin expression in human hepatocytes and mice. J. Biol. Chem. 294:13292-13303. PMID:31315930
Weiss, R.J., Spahn, P.N., Chiang, A.W.T., Li , J., Kellman, B.P., Benner, C., Glass, C.K., Gordts, P.L.S.M., Lewis, N.E. and Esko, J.D. (2020) ZNF263 is a novel transcriptional regulator of heparin biosynthesis. Proc. Natl. Acad. Sci. 117:9311-9317. PMID: 32277030
Sandoval, D.R., Toledo, A., Painter, C.D., Tota, E.M., Sheikh, M.O., West, A.M.V., Frank, M.M., Wells, L., Xu, D., Bicknell, R., Corbett, K.D. and Esko, J.D. (2020) Proteomics-based screening of the endothelial heparan sulfate interactome reveals that C-type lectin 14a (CLEC14A) is a heparin binding protein. J. Biol. Chem. 295:2804-2821. PMID:31964714. PMCID:7049958. Selected for a special virtual issue.
Spliid ,C.B., Toledo, A.G., Salanti, A., Esko, J.D. and Clausen, T.M. (2021) Beware, commercial chondroitinases vary in activity and substrate specificity. Glycobiology 31:103-115. PMID:32573715
Trabszo, C., Ramms, B., Chopra, P., Lüllmann-Rauch, R., Stroobants, S., Sproß, J., Jeschke, A., Schinke, T., Boons, G.-J., Esko, J.D., Lübke, T. and Dierks, T. Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate Biochem. J. (2020) 477:3433–3451. PMID:32856704
Weiss, R.J., Spahn, P.N., Chiang, A.W.T., Liu, Q., Li , J., Hamill, K.M., Rother, S., Clausen, T.M., Hoeksema, M.A., Timm, B.M., Godula, K., Glass, C.K., Tor, Y., Gordts, P.S.L.M., Lewis, N.E. and Esko, J.D. (2021) Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate. Nat. Chem. Biol. 17:684-692. PMID: 33846619
Thacker, B.E., Thorne, K.J., Cartwright, C., Park, J., Glass, K., Chea, A., Kellman, B.P., Lewis, N.E., Wang, Z., Di Nardo, A., Sharfstein, S.T., Jeske, W., Walenga, J., Hogwood, J., Gray, E., Mulloy, B., Esko, J.D., and Glass, C.A. (2022) Multiplex Genome Editing of Mammalian Cells for Producing Recombinant Heparin. Metab. Eng. 70:155-165. PMID:35038554