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Tudor staphylococcal nuclease is an evolutionarily conserved component of the programmed cell death degradome


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 animals1,2. Plants lack close homologues of caspases, but instead possess an ancestral family of cysteine proteases, metacaspases3,4. Although metacaspases are essential for PCD5,6,7, their natural substrates remain unknown4,8. 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 expression9,10,11,12,13,14,15, 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.

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Figure 1: Human TSN is a substrate for caspase-3 and is essential for cell viability.
Figure 2: Plant TSN is a substrate for metacaspase during developmental and stress-induced cell death.
Figure 3: Proteolytic cleavage inhibits TSN function.
Figure 4: TSN proteins are important for Arabidopsis pollen development and embryogenesis.
Figure 5: A proposed mechanistic model of caspase-mediated cleavage of TSN during PCD.

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The authors thank: L. Filonova (Swedish University of Agricultural Sciences) for microsurgery preparations of plant embryos; G. Swärdh (Swedish University of Agricultural Sciences) for Arabidopsis transformation and J. Dangl, A. Jones, C. Knorpp and S. Orrenius for comments on the manuscript. This work was supported by the Swedish Research Council (VR), the Swedish Cancer Society, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), the EC FP6 and FP7 Programs, the Carl Tryggers Foundation, the Pehrssons Fund, the Wenner-Gren Foundation, the Royal Swedish Academy of Agriculture and Forestry and the Ministerio de Ciencia e Innovacion, Spain. A.V. is a postdoctoral fellow of the Wenner-Gren Foundation.

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A.P.S, E.S., B.Z. and P.V.B. designed the research; J.F.S., A.V., A.P.S., E.I.S., A.G., E.M., B.S.T., S.R-N., A.A.Z.Jr, T.V., J.S., M.J.F., M.F.S., A.Z., U.S., E.S. and P.V.B. performed experiments and analysed data; P.J.H. and O.S. contributed new reagents/analytic tools; A.P.S., E.S., B.Z. and P.V.B. coordinated the study; A.P.S., O.S., B.Z. and P.V.B. wrote the paper; P.V.B. was responsible for the overall project.

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Correspondence to Andrei P. Smertenko or Peter V. Bozhkov.

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Sundström, J., Vaculova, A., Smertenko, A. et al. Tudor staphylococcal nuclease is an evolutionarily conserved component of the programmed cell death degradome. Nat Cell Biol 11, 1347–1354 (2009).

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