reporters are demonstrated as a valuable tool to dissect the fine specificities of the important glycoproteases, not only in terms of protein substrate motifs, but also with respect to the role of O-glycan structures given the capabilities to produce distinct glycoforms with the glycoengineered cell-based expression platform7,9,10).Recent studies demonstrate that specific mucins and mucin O-glycans have exciting biomedical potential. Mucins can disperse biofilms and disrupt bacterial aggregation11), and mucins and mucin O-glycans are recognized by bacterial sensors and inhibits virulence traits and quorum sensing12). However, these studies were performed with isolated heterogenous animal and human mucins and released O-glycans, so the molecular basis for these effects remain largely obscure, yet they clearly point to novel therapeutic applications of mucins. We believe our studies confirm the hypothesis that mucins contain unique molecular binding codes in their TRs, governed by particular patterns and structures of O-glycans. The TRs and their glycocodes may thus be considered the informational content of mucins, and importantly these glycocodes provide a much greater potential Referencesbinding epitome than the comparatively more limited repertoire of epitopes comprised of individual O-glycan structures available in humans.Our finding that defined mucin TR modules can be produced with programmable O-glycans will enable the microbiome community to integrate mucins in studies at a level and detail not previously envisioned. This may be a first steps towards a greater understanding of the complex functions of mucins in orienting our microbiomes, and establishment of the mucin display platform will widely open the mucin and microbiome fields for studies with homogeneous mucin libraries and for entirely new approaches to test and dissect the biophysical properties and the informational content of human mucins. Moreover, the ability to produce large quantities of mucin TR fragments provides a substantial first step towards sustainable manufacturing of natural mucins with wide potential use in biophysical and macromolecular sciences as well as biotech and biopharma industries (Figure 2). 1) Hansson, G.C. Mucus and mucins in diseases of the intestinal and respiratory tracts. J Intern Med 285, 479-490 (2019). 2) Werlang, C., Carcarmo-Oyarce, G. & Ribbeck, K. Engineering mucus to study and influence the microbiome. Nat Rev Mater 4, 134-145 (2019). 3) Narimatsu, Y. et al. An Atlas of Human Glycosylation Pathways Enables Display of the Human Glycome by Gene Engineered Cells. Mol Cell 75, 394- 4) Narimatsu, Y. et al. Genetic glycoengineering in mammalian cells. J Biol Chem 296, 100448 (2021). 5) *Bull, C. et al. Probing the binding specificities of human Siglecs by cell-based glycan arrays. Proc Natl Acad Sci U S A 118 (2021). 6) *Nason, R. et al. Display of the human mucinome with defined O-glycans by gene engineered cells. Nat Commun 12, 4070 (2021). 7) *Konstantinidi, A. et al. Exploring the glycosylation of mucins by use of O-glycodomain reporters recombinantly expressed in glycoengineered HEK293 8) *Sun, L. et al. Installation of O-glycan sulfation capacities in human HEK293 cells for display of sulfated mucins. J Biol Chem 298, 101382 (2022). 9) *Coelho, H. et al. Atomic and Specificity Details of Mucin 1 O-Glycosylation Process by Multiple Polypeptide GalNAc-Transferase Isoforms Unveiled * The publication supported by Mizutani foundation.407 e395 (2019).cells. J Biol Chem 298, 101784 (2022).by NMR and Molecular Modeling. JACS Au 2, 631-645 (2022).10) *Taleb, V. et al. Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut. Nat Commun 13, 4324 (2022).11) Wheeler, K.M. et al. Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Nat Microbiol 4, 2146-2154 (2019).12) Werlang, C.A. et al. Mucin O-glycans suppress quorum-sensing pathways and genetic transformation in Streptococcus mutans. Nat Microbiol 6, 574-583 (2021).115
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