Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.

Programmed cell death (PCD) is indispensable for eukaryotic development. In animals, PCD is executed by the caspase family of cysteine proteases. Plants do not have close homologues of caspases but possess a phylogenetically distant family of cysteine proteases named metacaspases. The cellular function of metacaspases in PCD is unknown. Here we show that during plant embryogenesis, metacaspase mcII-Pa translocates from the cytoplasm to nuclei in terminally differentiated cells that are destined for elimination, where it colocalizes with the nuclear pore complex and chromatin, causing nuclear envelope disassembly and DNA fragmentation. The cell-death function of mcII-Pa relies on its cysteine-dependent arginine-specific proteolytic activity. Accordingly, mutation of catalytic cysteine abrogates the proteolytic activity of mcII-Pa and blocks nuclear degradation. These results establish metacaspase as an executioner of PCD during embryo patterning and provide a functional link between PCD and embryogenesis in plants. Although mcII-Pa and metazoan caspases have different substrate specificity, they serve a common function during development, demonstrating the evolutionary parallelism of PCD pathways in plants and animals.embryo suspensor ͉ metacaspase ͉ nuclear degradation P rogrammed cell death (PCD) is indispensable for normal embryo development both in animals and in plants, where temporary, surplus, or aberrantly formed tissues and organs are removed for correct pattern formation (1, 2). The key morphogenetic event in plant embryogenesis is formation of the apicalbasal pattern via establishment of the proliferating embryo proper (apical) and the terminally differentiated suspensor (basal). Developmental programs of the embryo proper and the suspensor are closely coordinated, and imbalance causes embryonic defects or lethality (2-4). While the embryo proper gives rise to the plant, the suspensor functions during a brief period as a conduit of growth factors to the developing embryo and is subsequently eliminated by PCD (2). The terminal differentiation of the embryo suspensor is the earliest manifestation of cellular suicide in plant ontogenesis. However, the molecular mechanisms that regulate PCD in plant embryos are unknown.The nucleus is the major target of cell degradation machinery during PCD. Nuclear degradation processes encompass chromatin events (i.e., chromatin condensation and DNA fragmentation) and nuclear envelope events (i.e., lobing of the nuclear surface and disassembly of nuclear pore complex) that occur simultaneously in the same cell (2, 5). The structural organization of plant and animal nuclei is conserved (6), explaining why the morphological pattern of nuclear degradation is also conserved (2). However, the molecular composition of plant and animal nuclear envelopes is not conserved (6), implying that different molecular mechanisms are responsible for nuclear envelope events during PCD in plants.In animals, nuclear degradation during PCD is executed by a caspase family of cysteine proteases...

Programmed cell death (PCD) is executed by proteases, which cleave diverse proteins thus modulating their biochemical and cellular functions. Proteases of the caspase family and hundreds of caspase substrates constitute a major part of the PCD degradome in animals. Plants lack close homologues of caspases, but instead possess an ancestral family of cysteine proteases, metacaspases. Although metacaspases are essential for PCD, their natural substrates remain unknown. Here we show that metacaspase mcII-Pa cleaves a phylogenetically conserved protein, TSN (Tudor staphylococcal nuclease), during both developmental and stress-induced PCD. TSN knockdown leads to activation of ectopic cell death during reproduction, impairing plant fertility. Surprisingly, human TSN (also known as p100 or SND1), a multifunctional regulator of gene expression, is cleaved by caspase-3 during apoptosis. This cleavage impairs the ability of TSN to activate mRNA splicing, inhibits its ribonuclease activity and is important for the execution of apoptosis. Our results establish TSN as the first biological substrate of metacaspase and demonstrate that despite the divergence of plants and animals from a common ancestor about one billion years ago and their use of distinct PCD pathways, both have retained a common mechanism to compromise cell viability through the cleavage of the same substrate, TSN.

In plants, as in animals, programmed cell death (PCD) is a key process responsible for the elimination of unneeded structures and for overall shape remodeling during development [1]; however, the molecular mechanisms remain poorly understood. Despite the absence of canonical caspases in plants, dying plant cells show an increased proteolytic caspase-like activity [2]. Moreover, the cell death can be suppressed using synthetic [2] or natural [3] caspase inhibitors. This raises the question of whether plants have specific cysteine proteases with a role similar to metazoan caspases in the execution of PCD. Metacaspases are the best candidates to perform this role, because they contain a caspasespecific catalytic diad of histidine and cysteine as well as conserved caspase-like secondary structure [4,5]. Here we show the first experimental evidence for metacaspase function in the activation and/or execution of PCD in plants, and also demonstrate the fundamental requirement of plant metacaspase for embryogenesis.We explored the role of plant metacaspases in PCD using a model system of somatic embryogenesis of Norway spruce (Picea abies), where the pathway of embryo development (Figure 1A) resembles zygotic embryogeny, even though the embryo origin is different in each case (i.e., somatic cells in proembryogenic mass