4.8 Article

Extracellular endosulfatase Sulf-2 harbors a chondroitin/dermatan sulfate chain that modulates its enzyme activity

Journal

CELL REPORTS
Volume 38, Issue 11, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2022.110516

Keywords

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Funding

  1. Grenoble Instruct-ERIC center (ISBG) [UMS 3518 CNRS-CEA-UJF-EMBL]
  2. FRISBI [ANR-10-INBS-0502]
  3. GRAL
  4. Universite Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS [ANR-17-EURE-0003]
  5. CNRS
  6. GDR GAG [GDR 3739]
  7. Investissements d'avenir'' program Glyco@Alps [ANR-15-IDEX-02]
  8. Agence Nationale de la Recherche [ANR-12-BSV8-0023, ANR-17-CE11-0040, ANR-19-CE13-0031]
  9. Universite' Grenoble Alpes (UGA AGIR program)
  10. Swedish Research Council [2017-00955]
  11. Ingabritt and Arne Lundbergs Forskningsstiftelse
  12. Agence Nationale de la Recherche (ANR) [ANR-17-CE11-0040, ANR-19-CE13-0031] Funding Source: Agence Nationale de la Recherche (ANR)

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This study found that human HSulf-2 enzyme carries a chondroitin/dermatan sulfate glycosaminoglycan (GAG) chain, which regulates the enzyme's activity and is promoted by mammalian hyaluronidase.
Sulfs represent a class of unconventional sulfatases which provide an original post-synthetic regulatory mechanism for heparan sulfate polysaccharides and are involved in multiple physiopathological processes, including cancer. However, Sulfs remain poorly characterized enzymes, with major discrepancies regarding their in vivo functions. Here we show that human SuIf-2 (HSulf-2) harbors a chondroitin/dermatan sulfate glycosaminoglycan (GAG) chain, attached to the enzyme substrate-binding domain. We demonstrate that this GAG chain affects enzyme/substrate recognition and tunes HSulf-2 activity in vitro and in vivo. In addition, we show that mammalian hyaluronidase acts as a promoter of HSulf-2 activity by digesting its GAG chain. In conclusion, our results highlight HSulf-2 as a proteoglycan-related enzyme and its GAG chain as a critical non-catalytic modulator of the enzyme activity. These findings contribute to clarifying the conflicting data on the activities of the Sulfs.

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