Laminopathies and the long strange trip from basic cell biology to therapy

Abstract

The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases ("laminopathies"), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.

Figure 1. The nuclear lamina.

(A) The nuclear lamina is a meshwork of IFs localized primarily to the nucleoplasmic face of the inner nuclear membrane (shown schematically in red). The lamins interact with several integral proteins of the inner nuclear membrane, including lamin B receptor (LBR), MAN1 (encoded by the LEMD3 gene), emerin, lamina-associated polypeptide 1 (LAP), LAP2β, small nesprin 1 isoforms, and SUNs. SUNs interact with large nesprin 2 isoforms, integral proteins of the outer nuclear membrane, which also interact with actin, linking the nuclear lamina to the cytoskeleton. (B) In humans, 3 genes encode nuclear lamins. LMNA on chromosome 1q21.2 encodes the A-type lamins, with prelamin A and lamin C generated by alternative RNA splicing being the major somatic cell isoforms. Prelamin A has 98 unique amino acids and lamin C 6 unique amino acids at their carboxyl terminus (gray striping). LMNB1 on chromosome 5q23.3–q31.1 encodes lamin B1, and LMNB2 on chromosome 19p13.3 encodes lamin B2, the somatic cell B-type lamins. All the lamins have conserved α-helical rod domains and variable head and tail domains preceding and following the central rod domain. The nuclear localization signals are located in the tail domain (indicated in red). Prelamin A, lamin B1, and lamin B2 have carboxyl-terminal CaaX motifs, a signal for protein farnesylation.

Figure 2. Schematic diagram outlining the posttranslational processing of nuclear lamins.

Prelamin A and B-type lamins undergo 3 sequential posttranslational processing steps. First, the cysteine of the carboxyl-terminal CaaX motif is farnesylated by protein FTase. Second, the –aaX is clipped off. For prelamin A, this is likely a redundant activity of RCE1 and ZMPSTE24. Third, the newly exposed carboxyl-terminal farnesylcysteine is methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). Prelamin A undergoes another step in which the carboxyl-terminal 15 amino acids, including the farnesylcysteine methyl ester, are clipped off by ZMPSTE24 and degraded, generating mature lamin A. In the setting of ZMPSTE24 deficiency, the final endoproteolytic cleavage does not occur, leading to the accumulation of a farnesylated and methylated prelamin A. ZMPSTE24 deficiency causes a severe progeroid disorder, RD. In HGPS, an alternative splicing event results in a 50–amino acid deletion in prelamin A, removing the site for the final endoproteolytic cleavage step. Thus, mature lamin A cannot be produced, and cells accumulate a mutant prelamin A that terminates with a farnesylcysteine α-methyl ester.

Figure 3. Studies from Lmna^H222P/H222P knockin mice and Emd-knockout mice suggest that activation of ERK and/or JNK underlies the development of cardiomyopathy.

Cardiomyocytes in normal hearts of wild-type mice exhibit detectable ERK and JNK activation, as judged by low levels of expression of downstream transcription factors such as Elk1, Elk4, Aft2, and Aft4 (left panel). Both ERK and JNK signaling are increased in hearts from mice harboring the H222P point mutation in Lmna, whereas ERK is activated in hearts of Emd-knockout mice (red arrows; middle panel). Phosphorylation and nuclear translocation of ERK and JNK modulate gene expression, leading to dilated cardiomyopathy (middle panel). Currently, it is unclear how alterations in A-type lamins or the loss of emerin lead to the activation of ERK and/or JNK. Studies in Lmna^H222P/H222P mice have shown that pharmacological inhibition of MEK, the kinase that phosphorylates ERK, can prevent the development of cardiomyopathy at 16 weeks of age (right panel).