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Latent transforming growth factor beta-binding proteins-2 and -3 inhibit the proprotein convertase 5/6A

Xiaowei Sun1, Rachid Essalmani1, Delia Susan-Resiga1

  • 1Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.

The Journal of Biological Chemistry
|June 25, 2011
PubMed

Insights

Latent TGFβ-binding proteins (LTBPs) bind proprotein convertase 5/6A (PC5/6A) in the endoplasmic reticulum, inhibiting its extracellular activity. This LTBP-mediated regulation impacts PC5/6A levels and function, particularly in bone and lung development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Developmental Biology

Background:

  • Proprotein convertase 5/6 (PC5/6) is a crucial secretory protease involved in development, with deficiencies causing severe homeotic transformations.
  • Impaired processing of growth differentiating factor 11 (proGdf11) has been linked to PC5/6 deficiency-related defects in bone and lung morphogenesis.
  • Latent TGFβ-binding proteins (LTBPs) are extracellular matrix proteins with known roles in TGFβ signaling, but their interaction with proprotein convertases is less understood.

Purpose of the Study:

  • To investigate the role of LTBP-2 and LTBP-3 in the extracellular processing of proGdf11 by PC5/6A.
  • To elucidate the mechanism by which LTBPs regulate PC5/6A activity and localization.
  • To explore the potential implications of this regulation in developmental processes.

Main Methods:

  • Co-expression of PC5/6A and LTBPs in cell culture systems.
  • Measurement of PC5/6A levels in cell media and activity assays.
  • In situ hybridization to analyze mRNA co-localization of PC5/6 and LTBP-3 in mouse tissues.

Main Results:

  • LTBP-2 and LTBP-3 were found to inhibit the extracellular processing of proGdf11 by PC5/6A.
  • LTBPs bind to the zymogen form of PC5/6A (proPC5/6A) in the endoplasmic reticulum, facilitating its secretion and sequestration in the extracellular matrix.
  • This interaction leads to reduced extracellular PC5/6A activity and lower levels in the media, without affecting other convertases like Furin or PACE4.
  • Co-expression with LTBPs significantly decreased the secreted protease activity of PC5/6A and a variant lacking the C-terminal domain.
  • Extensive co-localization of PC5/6 and LTBP-3 mRNAs was observed in developing mouse tissues.

Conclusions:

  • This study reveals a novel mechanism of proprotein convertase regulation, where LTBPs sequester inactive proPC5/6A in the extracellular matrix.
  • LTBP binding in the endoplasmic reticulum allows proPC5/6A to exit while maintaining it in an inactive zymogen form extracellularly.
  • This represents a new regulatory pathway for PC5/6A activity, particularly relevant in tissues like bone and lung where PC5/6 and LTBP-3 expression overlap during development.

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