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NRAS is unique among RAS proteins in requiring ICMT for trafficking to the plasma membrane

Ian M Ahearn1,2,3, Helen R Court2, Farid Siddiqui4

  • 1The Ronald O Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, USA ian.ahearn@nyulangone.org.

Life Science Alliance
|February 13, 2021
PubMed

Insights

Carboxyl methylation by Isoprenylcysteine carboxyl methyltransferase (ICMT) is crucial for NRAS delivery to the plasma membrane. This process ensures proper palmitoylation, chaperone binding, and Golgi trafficking of NRAS.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Isoprenylcysteine carboxyl methyltransferase (ICMT) modifies C-terminus of CaaX proteins, including RAS.
  • RAS proteins traffic to membranes differently due to variable regions and palmitoylation.
  • NRAS uniquely requires ICMT for plasma membrane delivery, possessing only one palmitoylation site.

Purpose of the Study:

  • To investigate the role of ICMT in NRAS trafficking and membrane delivery.
  • To understand how ICMT activity affects NRAS palmitoylation and association with PDE6δ.
  • To elucidate the impact of ICMT on NRAS flux through the Golgi apparatus.

Main Methods:

  • Utilized photoactivation and Fluorescence Recovery After Photobleaching (FRAP) of GFP-NRAS.
  • Assessed acylation levels in the presence and absence of ICMT.
  • Examined NRAS association with the prenyl-protein chaperone PDE6δ.

Main Results:

  • ICMT is essential for NRAS delivery to the plasma membrane.
  • Acylation of NRAS was diminished without ICMT.
  • ICMT absence increased Golgi flux of NRAS, independent of palmitoylation.
  • ICMT was required for NRAS binding to PDE6δ and anterograde Golgi trafficking.

Conclusions:

  • Carboxyl methylation of NRAS by ICMT is vital for efficient palmitoylation.
  • ICMT facilitates PDE6δ binding and homeostatic Golgi flux for NRAS.
  • These ICMT-dependent processes are critical for directing NRAS to the plasma membrane.

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