PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Cereblon (CRBN) is a key target for thalidomide and lenalidomide, recognizing substrates with C-terminal cyclic imide modifications.
• The enzyme responsible for regulating these modifications and linking substrates to CRBN has remained unidentified.

Purpose of the Study:

• To identify the enzyme that promotes C-terminal cyclic imide formation on CRBN substrates.
• To elucidate the biological pathway regulated by this enzyme and CRBN.

Main Methods:

• Investigated the role of protein carboxymethyltransferase (PCMT1) in C-terminal cyclic imide formation.
• Assessed the co-regulation of glutamine synthetase (GLUL) and inorganic pyrophosphatase 1 (PPA1) by PCMT1 and CRBN.
• Utilized in vitro, cellular, and in vivo models, including CRBN knockout mice.

Main Results:

• PCMT1 was identified as the enzyme that promotes C-terminal cyclic imide formation on CRBN substrates.
• PCMT1 and CRBN were shown to co-regulate GLUL and PPA1 levels.
• This regulation is linked to the proepileptic phenotype observed in CRBN knockout mice.

Conclusions:

• The discovery of PCMT1 reveals a novel enzymatic pathway regulating CRBN substrates via C-terminal cyclic imide modification.
• This pathway is perturbed by thalidomide derivatives, offering a biochemical link between CRBN and various biological processes.
• The findings provide a new understanding of CRBN biology and its modulation by therapeutic agents.