Abstract
Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide-mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide-mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.
| Original language | English |
|---|---|
| Article number | e111869 |
| Journal | EMBO Journal |
| Volume | 42 |
| Issue number | 2 |
| DOIs | |
| State | Published - 16 Jan 2023 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
Funding
The authors thank Diego Butera and Philip Hogg for confirming the observation that Vwf multimers form in QSOX1 KO mice. Shalev Itzkovitz is gratefully acknowledged for helpful discussions. David Morgenstern validated St6gal1 mutants using mass spectrometry. Avital Sarusi‐Portuguez assisted with single‐cell expression analysis. EM studies were conducted at the Irving and Cherna Moskowitz Center for Nano and Bio‐Nano Imaging at the Weizmann Institute of Science. Research was supported by the European Research Council under the European Union's Seventh Framework Programme (ERC grant agreement 310649 to DF), the Mizutani Foundation for Glycoscience (to DF), the Israel Science Foundation (grant 2660/20 to DF and TI), the Center for Scientific Excellence at the Weizmann Institute of Science (to DF), the National Institutes of Health (NIH) (grants HL080396 and HL130938 to CME), and the Cystic Fibrosis Foundation (JARAMI20F0 to AMJ). The authors thank Diego Butera and Philip Hogg for confirming the observation that Vwf multimers form in QSOX1 KO mice. Shalev Itzkovitz is gratefully acknowledged for helpful discussions. David Morgenstern validated St6gal1 mutants using mass spectrometry. Avital Sarusi-Portuguez assisted with single-cell expression analysis. EM studies were conducted at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. Research was supported by the European Research Council under the European Union's Seventh Framework Programme (ERC grant agreement 310649 to DF), the Mizutani Foundation for Glycoscience (to DF), the Israel Science Foundation (grant 2660/20 to DF and TI), the Center for Scientific Excellence at the Weizmann Institute of Science (to DF), the National Institutes of Health (NIH) (grants HL080396 and HL130938 to CME), and the Cystic Fibrosis Foundation (JARAMI20F0 to AMJ).
| Funders | Funder number |
|---|---|
| Center for Scientific Excellence at the Weizmann Institute of Science | |
| National Institutes of Health | HL130938, HL080396 |
| Cystic Fibrosis Foundation | JARAMI20F0 |
| Mizutani Foundation for Glycoscience | |
| Seventh Framework Programme | 310649 |
| European Commission | |
| Weizmann Institute of Science | |
| Israel Science Foundation | 2660/20 |
| Seventh Framework Programme |
Keywords
- colon
- glycosyltransferases
- mucus
- redox homeostasis
- sulfhydryl oxidase