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Manganese-induced trafficking and turnover of GPP130 is mediated by sortilin

Swati Venkat1, Adam D Linstedt2

  • 1Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.

Molecular Biology of the Cell
|August 4, 2017
PubMed

Insights

Manganese (Mn) prevents Shiga toxin-1 cell death by causing the Golgi protein GPP130 to aggregate and be degraded in lysosomes. This process involves sortilin-dependent and independent pathways for aggregated Golgi proteins.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Toxicology

Background:

  • Shiga toxin-1 induces cell death by hijacking cellular trafficking pathways.
  • GPP130, a Golgi membrane protein, acts as an endosome-to-Golgi trafficking receptor for Shiga toxin-1.
  • Elevated, nontoxic doses of manganese (Mn) have been observed to protect cells against Shiga toxin-1-induced cell death.

Purpose of the Study:

  • To elucidate the mechanism by which manganese protects cells from Shiga toxin-1.
  • To investigate the role of GPP130 aggregation and lysosomal degradation in cellular protection.
  • To identify the sorting mechanisms responsible for targeting aggregated Golgi proteins to lysosomes.

Main Methods:

  • Cell-based assays to assess cell death and protein localization.
  • Biochemical techniques to study protein-protein interactions and aggregation.
  • Use of the self-interacting FM domain and specific Golgi proteins like GPP130 and galactosyltransferase.
  • Investigation of the role of the sorting receptor sortilin.

Main Results:

  • Manganese induces GPP130 aggregation in the Golgi, leading to its lysosomal degradation.
  • This aggregation and subsequent lysosomal trafficking protect cells from Shiga toxin-1.
  • Mn-induced GPP130 exit from the trans-Golgi network (TGN) is mediated by sortilin.
  • Aggregation of other Golgi proteins, like galactosyltransferase, can also lead to lysosomal degradation via sortilin-independent pathways.

Conclusions:

  • Protein aggregation within the Golgi can trigger lysosomal degradation pathways.
  • Both sortilin-dependent and sortilin-independent mechanisms exist for targeting aggregated Golgi membrane proteins to lysosomes.
  • Understanding these pathways offers potential therapeutic strategies against toxin-induced cellular damage.

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