Getting lamin B1 processed and organized

Lamins are the building blocks of the nuclear lamina, a complex polymer attached to the nuclear envelope that is thought to be important for nuclear stability, chromatin organization, and gene expression. On page 1223, Maske et al. identify the protease responsible for processing lamin B1, demonstrate the existence of a nuclear receptor specific for carboxymethylated lamin B1, and show that posttranslational processing may control the localization of this lamin into subdomains within the nuclear envelope.

After being farnesylated, the COOH-terminal CAAX domain of lamin B1 is cleaved by an endoprotease, and the new COOH terminus of the protein is then methylated by the enzyme Icmt. Using a monoclonal antibody that distinguishes proteolyzed from unproteolyzed lamin B1, the authors determined that proteolysis specifically requires the CAAX endoprotease Rce1. Separate pools of farnesylated but unproteolyzed and proteolyzed but unmethylated lamin B1 appear in the nucleus, but retention of the protein's COOH terminus in the nuclear envelope requires carboxymethylation, indicating that a nuclear receptor specifically recognizes the fully processed form of the protein. When farnesylation is inhibited, the residual mature form occupies defined subdomains of the nuclear lamina, and the authors have preliminary evidence that these subdomains are also present in untreated cells.

The results suggest that methylation of lamin B1 is a novel mechanism controlling the higher order organization of the nucleus. Lamin B1 interacts with chromatin, so the protein's controlled localization to subdomains of the lamina might organize interacting chromatin into similar domains. The authors are now trying to identify the nuclear receptor for carboxymethylated lamin B1.

Since the well-known oncogene ras also requires processing of its CAAX domain, CAAX endoproteases, including Rce1, are popular targets for a new generation of experimental anticancer drugs. It was initially thought that CAAX processing was unnecessary in nondividing cells, but the new findings show that interfering with lamin B1 processing disrupts the integrity of the nuclear envelope, highlighting the potential for unforeseen side effects with the new drugs. ▪