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<p>Sialic acid <i>O</i>-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-<i>O</i>-acetylation. Under conditions that enable the formation of 7,9-di-<i>O</i>-acetylated sialoglycans, genetic inactivation of SLC33A1 impaired di-<i>O</i>-acetylation, but unexpectedly, still enabled mono-<i>O</i>-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-<i>O</i>-acetylation through SLC33A1-dependent luminal acetylation and SLC33A1-independent transmembrane acetylation.</p>

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Interplay of SLC33A1-dependent and -independent Golgi sialic acid O-acetylation in CASD1 catalysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Malena Albers,
  • Lydia Bosse,
  • Larissa Schröter,
  • Anna-Maria T. Junemann,
  • Charlotte Rossdam,
  • Maike Hartmann,
  • Melanie Grove,
  • Thomas Litfin,
  • Anna-Sophia Egger,
  • Marcel Kwiatkowski,
  • Kathrin Thedieck,
  • Georg Zocher,
  • Falk F. R. Buettner,
  • Alpeshkumar K. Malde,
  • Mark von Itzstein,
  • Martina Mühlenhoff

摘要

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.