Investigating the purpose of prelamin A processing

Abstract

Lmna yields two major protein products in somatic cells, lamin C and prelamin A. Mature lamin A is produced from prelamin A by four posttranslational processing steps-farnesylation of a carboxyl-terminal cysteine, release of the last three amino acids of the protein, methylation of the farnesylcysteine, and the endoproteolytic release of the carboxyl-terminal 15 amino acids of the protein (including the farnesylcysteine methyl ester). Although the posttranslational processing of prelamin A has been conserved in vertebrate evolution, its physiologic significance remains unclear. Here we review recent studies in which we investigated prelamin A processing with Lmna knock-in mice that produce exclusively prelamin A (Lmna(PLAO)), mature lamin A (Lmna(LAO)) or nonfarnesylated prelamin A (Lmna(nPLAO)). We found that the synthesis of lamin C is dispensable in laboratory mice, that the direct production of mature lamin A (completely bypassing all prelamin A processing) causes no discernable pathology in mice, and that exclusive production of nonfarnesylated prelamin A leads to cardiomyopathy.

Keywords: cardiomyopathy; prelamin A; progeria; protein farnesylation; restrictive dermopathy.

Figure 1

Survival curves for Lmna^+/+, Lmna^nPLAO/+ and Lmna^nPLAO/− mice. The survival time for male Lmna^nPLAO/− mice was shorter than for Lmna^+/+ or Lmna^nPLAO/+ mice (n = 4 for each group) (p = 0.002). Previous studies showed that male Lmna^nPLAO/nPLAO mice had an average survival time of 38.5 weeks (a milder phenotype than Lmna^nPLAO/− mice), suggesting that nonfarnesylated prelamin A is a poorly functioning lamin.

Figure 2

The effects of disrupting A-type lamin synthesis and processing in laboratory mice. (A) Wild-type mice produce both lamin C and prelamin A. Prelamin A then undergoes four sequential posttranslational processing steps to generate mature lamin A. (B) Lmna^−/− mice produce neither lamin A nor lamin C. These mice have muscular dystrophy and die at 5–6 weeks of age. (C) Lmna^LCO/LCO mice produce only lamin C. These mice appear to be phenotypically normal. (D) Lmna^PLAO/PLAO mice do not produce lamin C. The prelamin A produced by these mice is efficiently converted to mature lamin A. These mice also appear to be normal. (E) Lmna^LAO/LAO mice produce mature lamin A directly, bypassing prelamin A synthesis and processing. These mice make no lamin C. Like Lmna^LCO/LCO and Lmna^PLAO/PLAO mice, Lmna^LAO/LAO mice appear to be normal. (F) Lmna^nPLAO/nPLAO produce exclusively nonfarnesylated prelamin A. Because of a cysteine-to-serine substitution in prelamin A's CaaX motif, the prelamin A cannot be farnesylated. These mice develop dilated cardiomyopathy and have reduced survival. (G) Zmpste24-deficient mice produce both lamin C and prelamin A, but the final endoproteolytic step does not occur, resulting in the accumulation of farnesylated prelamin A. These mice display multiple progeria-like disease phenotypes., (H) In addition to making normal lamin C and prelamin A from one allele, Lmna^HG/+ mice make a prelamin A with a 50-amino acid internal deletion (from the Lmna^HG allele). This deletion prevents the final, ZMPSTE24-mediated, endoproteolytic step from occurring and leads to the accumulation of a farnesylated and truncated form of prelamin A called progerin. Despite the presence of normal forms of lamin A and lamin C, these mice develop progeria-like disease phenotypes., (I) Lmna^nHG/+ mice are identical to LmnaHG/+ mice except that the truncated prelamin A generated from the Lmna^nHG allele cannot be farnesylated (due to a cysteine-to-serine substitution in the CaaX motif), leading to the accumulation of nonfarnesylated progerin. These mice also have progeria, though it is somewhat less severe than that found in Lmna^HG/+ mice.