Related Experiment Video

Updated: Mar 6, 2026

In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination
07:58

In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination

Published on: January 2, 2026

499

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates

Thang Van Nguyen1, Jing Li1, Chin-Chun Jean Lu2

  • 1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.

Proceedings of the National Academy of Sciences of the United States of America
|March 22, 2017
PubMed

Insights

Valosin-containing protein (VCP)/p97 facilitates the degradation of ubiquitylated glutamine synthetase (GS). Impaired p97 function leads to GS accumulation, revealing a link between CRBN and p97 pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Glutamine synthetase (GS) is crucial for amino acid metabolism.
  • CRBN (Cereblon) is a target of immunomodulatory drugs and recognizes an acetyl degron on GS.
  • GS degradation is induced by glutamine and mediated by CRBN.

Purpose of the Study:

  • To investigate the role of valosin-containing protein (VCP)/p97 in the degradation of ubiquitylated GS.
  • To explore the relationship between CRBN and p97 pathways in protein degradation.

Main Methods:

  • Cellular assays to monitor GS levels.
  • Protein degradation assays.
  • Analysis of ubiquitylated protein substrates.

Main Results:

  • VCP/p97 promotes the degradation of ubiquitylated GS.
  • GS accumulates in cells with compromised p97 function.
  • p97 is essential for the degradation of CRBN neo-substrates, including IKZF1, IKZF3, CK1α, and GSPT1.

Conclusions:

  • VCP/p97 is a key player in the proteasomal degradation of ubiquitylated GS.
  • The CRL4CRBN E3 ligase and p97 pathways are intimately linked.
  • This interaction is critical for regulating GS levels and potentially other CRBN substrates.
Keywords:
CRBNVCP/p97degradationglutamine synthetasesubstrates

More Related Videos

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.9K
Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae09:05

Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae

Published on: April 18, 2016

30.1K

Related Concept Videos

Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
9.1K
Regulated Protein Degradation02:58

Regulated Protein Degradation

3.3K
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.4K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
5.4K
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
12.0K
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

3.5K