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A Golgi rhomboid protease Rbd2 recruits Cdc48 to cleave yeast SREBP

Jiwon Hwang1, Diedre Ribbens1, Sumana Raychaudhuri1

  • 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The EMBO Journal
|September 23, 2016
PubMed

Insights

Fungal growth under low oxygen requires sterol regulatory element-binding protein (SREBP) processing. A novel protease, Rbd2, and Cdc48 are essential for SREBP activation, controlling its balance between processing and degradation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Mycology

Background:

  • Fungal pathogens require sterol regulatory element-binding protein (SREBP) activation for virulence.
  • Hypoxic growth necessitates SREBP transcription factors.
  • Proteolytic release of SREBP from the membrane under low oxygen involves the Dsc E3 ligase complex.

Purpose of the Study:

  • Identify novel factors involved in SREBP processing under hypoxia.
  • Elucidate the mechanism of SREBP proteolytic release.
  • Investigate the role of Rbd2 and Cdc48 in SREBP regulation.

Main Methods:

  • Genetic interaction arrays
  • Epistasis analysis
  • APEX2 proximity biotinylation
  • Proteolytic cleavage assays

Main Results:

  • Rbd2, a rhomboid family protease, is identified as essential for SREBP proteolytic processing.
  • Rbd2 is a Golgi-localized protease that cleaves the transmembrane segment of substrates.
  • Dsc E3 ligase acts on SREBP before Rbd2-mediated cleavage.
  • Rbd2 binds the AAA-ATPase Cdc48 via a C-terminal SHP box, and this interaction is crucial for SREBP cleavage.
  • Cdc48 likely recruits ubiquitinylated substrates for processing.
  • In the absence of Rbd2, SREBP precursor is proteasomally degraded.

Conclusions:

  • Rbd2 is a key protease regulating SREBP activation under hypoxia.
  • The Rbd2-Cdc48 interaction is critical for SREBP processing, balancing activation and degradation.
  • Rbd2 activity determines the fate of SREBP, preventing its proteasomal degradation.
Keywords:
SREBPCdc48/p97intramembrane proteolysisrhomboidubiquitin

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