Interplay of SLC33A1-dependent and -independent Golgi sialic acid O-acetylation in CASD1 catalysis
Sialic acid O-acetylation is implicated in the modulation of sialoglycan recognition and ganglioside biology. The sugar modification is catalyzed by CASD1, a Golgi membrane protein that encompasses a luminal catalytic domain and a multipass transmembrane domain. The mechanism of how acetyl-CoA is provided to the Golgi remains poorly understood. Here, we show that the acetyl-CoA transporter SLC33A1 provides acetyl-CoA to the luminal domain of CASD1 and that patient-derived SLC33A1 variants linked to inherited neurodevelopmental and neurodegenerative disorders impair ganglioside 9-O-acetylation. Under conditions that enable the formation of 7,9-di-O-acetylated sialoglycans, genetic inactivation of SLC33A1 impaired di-O-acetylation, but unexpectedly, still enabled mono-O-acetylation. Structure prediction and site-directed mutagenesis revealed a second active site in CASD1 that shares striking similarities with the catalytic acetyl-CoA binding transmembrane tunnel of the lysosomal acetyltransferase HGSNAT. Together, our data provide strong evidence that CASD1 has dual functionalities and catalyzes 7,9-di-O-acetylation through SLC33A1-dependent luminal acetylation and SLC33A1-independent transmembrane acetylation.
Authors
- Malena Albers
- Larissa Schröter
- Charlotte Rossdam (ORCID: https://orcid.org/0000-0001-5353-782X)
- Kathrin Thedieck (ORCID: https://orcid.org/0000-0002-9069-2930)
- Thomas Litfin (ORCID: https://orcid.org/0000-0002-4863-3865)
- Anna-Sophia Egger (ORCID: https://orcid.org/0000-0002-5204-7121)
- Georg Zocher (ORCID: https://orcid.org/0000-0001-8711-2088)
- Martina Mühlenhoff (ORCID: https://orcid.org/0000-0002-6070-8241)
- Alpeshkumar K. Malde (ORCID: https://orcid.org/0000-0002-8181-1619)
- Melanie Grove
- Mark von Itzstein (ORCID: https://orcid.org/0000-0001-6302-7524)
- Marcel Kwiatkowski (ORCID: https://orcid.org/0000-0002-5804-6031)
- Maike Hartmann
- F F R Buettner
- Anna-Maria T. Junemann
- Lydia Bosse
Institutions
- Griffith University (AU)
- University of Augsburg (DE)
- German Cancer Research Center (DE)
- Universität Innsbruck (AT)
- University of Zurich (CH)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- UNSW Sydney (AU)
- Medizinische Hochschule Hannover (DE)
- Ruhrlandklinik (DE)
- Düsseldorf University Hospital (DE)
- Essen University Hospital (DE)
- West German Heart and Vascular Center Essen (DE)
- Heinrich Heine University Düsseldorf (DE)
- University of Bergen (NO)
- University of Duisburg-Essen (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1038/s41467-026-71333-y
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministère de l'Économie, de la Science et de l'Innovation - Québec
- Queensland Cyber Infrastructure Foundation
- Australian Government
- European Commission
- Deutsche Forschungsgemeinschaft
- Griffith University
- HORIZON EUROPE Framework Programme
- Medical Research Council
- National Health and Medical Research Council