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

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

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

Purpose of the Study:

• To identify the enzyme that regulates the formation of C-terminal cyclic imides on CRBN substrates.
• To elucidate the biological pathway connecting substrates to CRBN mediated by this enzyme.

Main Methods:

• Investigated the role of protein carboxymethyltransferase (PCMT1) in the formation of C-terminal cyclic imides.
• Assessed the coregulation of metabolic enzymes by PCMT1 and CRBN in vitro, in cells, and in vivo.
• Examined the association of this regulation with the proepileptic phenotype in CRBN knockout mouse models.

Main Results:

• Identified PCMT1 as the enzyme that promotes the formation of C-terminal cyclic imides on C-terminal asparagine residues of CRBN substrates.
• Demonstrated that PCMT1 and CRBN coregulate metabolic enzymes like glutamine synthetase and inorganic pyrophosphatase 1.
• Linked this coregulation to the proepileptic phenotype observed in CRBN knockout mice.

Conclusions:

• The discovery of PCMT1 reveals a previously unknown enzymatic pathway regulating CRBN substrates via C-terminal cyclic imides.
• This pathway provides a biochemical basis for understanding how thalidomide derivatives affect biological processes mediated by CRBN.