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Determining Membrane Protein Topology Using Fluorescence Protease Protection (FPP)
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Published on: April 20, 2015

CD74 is a member of the regulated intramembrane proteolysis-processed protein family

Shirly Becker-Herman1, Galit Arie, Helena Medvedovsky

  • 1Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.

Molecular Biology of the Cell
|August 19, 2005
PubMed

Insights

Regulatory proteins like transcription factors are activated by cleavage. CD74 (invariant chain, Ii) undergoes regulated intramembrane proteolysis (RIP), releasing an active fragment that triggers gene transcription via NF-kappaB.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Protein Regulation

Background:

  • Regulatory proteins, including transcription factors, are often kept dormant until activated by specific cues.
  • A novel mechanism involves proteolytic cleavage to mobilize dormant transcription factors, which are initially bound to membrane proteins.
  • This process, known as regulated intramembrane proteolysis (RIP), is crucial for various biological processes in both prokaryotes and eukaryotes.

Purpose of the Study:

  • To investigate the role of CD74 (invariant chain, Ii) in regulated intramembrane proteolysis (RIP).
  • To determine how CD74 processing leads to the activation of transcription factors.
  • To elucidate the signaling pathway initiated by the intracellular domain of CD74.

Main Methods:

  • Analysis of CD74 processing within endocytic compartments.
  • Detection of CD74 intramembrane cleavage and release of its intracellular domain (CD74-ICD).
  • Nuclear translocation studies of CD74-ICD and its effect on transcription factor activation.

Main Results:

  • CD74 ectodomain processing in endocytic compartments is necessary for its intramembrane cleavage.
  • Intramembrane cleavage liberates the CD74 intracellular domain (CD74-ICD).
  • CD74-ICD translocates to the nucleus and activates the p65 subunit of NF-kappaB, mediating gene transcription.

Conclusions:

  • CD74 is a novel member of the regulated intramembrane proteolysis (RIP)-processed protein family.
  • The CD74 signaling pathway involves nuclear translocation of CD74-ICD to activate NF-kappaB.
  • This mechanism highlights a new pathway for regulating gene transcription through membrane protein processing.

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