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. 2021 Apr 28;31(8):988–1004. doi: 10.1093/glycob/cwab033

Fig. 8.

Fig. 8

O-linked glucose-β1-3fucose disaccharide modification of TSRs is important for secretion and extracellular assembly of B3GLCT substrates. Impaired CSF flow in B3glct mutants likely results from the combined effects of the mutation on multiple substrates by impacting the efficiency of substrate secretion and/or extracellular assembly/function of substrates. (A) B3GLCT/POFUT2 modification facilitates stabilization of ADAMTS20 and ADAMTS9 TSR folds and promotes efficient secretion of these substrates, especially ADAMTS20 (Holdener et al. 2019). (A, top left) We propose that postnatal expression of Adamts20 and Adamts9 in the ependymal cells promotes translational polarity of the ependymal cell cilia by altering properties of the matrix and/or a noncanonical role in regulating cilia. (A, top right) In B3glct mutants, defects in ADAMTS20 and ADAMTS9 secretion (Holdener et al. 2019) result in impaired translational polarity of ependymal cells in B3glct mutants. (B) We propose that B3GLCT/POFUT2 modification of SSPO is not only important for efficient trafficking of SSPO but is also likely important for extracellular assembly of SSPO. (B, left) In wild-type subcommissural organ cells, SSPO and BiP colocalize within the ER. As SSPO transits to the Golgi, BiP is returned to the ER, and SSPO is packaged into secretory vesicles, processed and secreted. Secreted SSPO is found both as soluble fragments in the CSF and also assembles via intermolecular and intramolecular disulfide bonds (Munoz et al. 2019). (B, right) In B3glct mutants, intracellular levels of SSPO are reduced consistent with a role for the O-linked disaccharide in stabilizing the TSR fold. However, the continued association of SSPO with BiP in secretory vesicles and Reissner’s fiber suggests a defect in intra- or intermolecular assemble of SSPO, raising the possibility for an alternate role for the disaccharide in protecting the TSR disulfide bond from inappropriate extracellular intermolecular isomerization. Red triangle and blue circle indicate fucose and glucose, respectively, and black circle indicates glucose is absent. Abbreviations: ER, endoplasmic reticulum; SV, secretory vesicles.