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Primary cilium suppression by SREBP1c involves distortion of vesicular trafficking by PLA2G3

Hannah Laura Gijs1, Nicolas Willemarck1, Frank Vanderhoydonc1

  • 1Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, B-3000 Leuven, Belgium.

Molecular Biology of the Cell
|April 24, 2015
PubMed

Insights

Aberrant sterol regulatory element-binding protein 1c (SREBP1c) activation suppresses primary ciliogenesis by upregulating phospholipase A2 group III (PLA2G3), disrupting vesicular transport. Inhibiting PLA2G3 normalizes ciliogenesis in SREBP1c-overexpressing cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Primary cilia formation is crucial for cellular function and implicated in various pathologies.
  • Aberrant activation of sterol regulatory element-binding protein 1c (SREBP1c), a lipogenic transcription factor, is linked to suppressed ciliogenesis, particularly in cancer cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which SREBP1c suppresses primary ciliogenesis.
  • To identify novel molecular targets for restoring ciliogenesis in SREBP1c-driven pathologies.

Main Methods:

  • Comparative analysis of ciliogenesis regulators and SREBP1 targets.
  • Utilized RNA interference and chemical inhibitors to study phospholipase A2 group III (PLA2G3) function.
  • Assessed endosomal recycling and vesicular transport using transferrin and Rab11 localization.

Main Results:

  • Phospholipase A2 group III (PLA2G3) was identified as a gene upregulated by SREBP1c, inhibiting ciliogenesis.
  • PLA2G3 inhibition via RNA interference or chemical means rescued SREBP1c-induced ciliogenesis defects.
  • SREBP1c and PLA2G3 mediated repression involved impaired endosomal recycling and vesicular transport, evidenced by altered transferrin and Rab11 localization.
  • Increased lysophosphatidylcholine and lysophosphatidylethanolamine levels were associated with the observed ciliogenesis defects.

Conclusions:

  • Aberrant SREBP1c activation suppresses primary ciliogenesis through PLA2G3-mediated disruption of vesicular trafficking.
  • PLA2G3 represents a potential therapeutic target for normalizing ciliogenesis in SREBP1c-overexpressing cells, including cancer cells.

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