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Mitochondrial membrane remodelling regulated by a conserved rhomboid protease

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Abstract

Rhomboid proteins are intramembrane serine proteases that activate epidermal growth factor receptor (EGFR) signalling in Drosophila1. Rhomboids are conserved throughout evolution2,3,4,5, and even in eukaryotes their existence in species with no EGFRs implies that they must have additional roles. Here we report that Saccharomyces cerevisiae has two rhomboids, which we have named Rbd1p and Rbd2p. RBD1 deletion results in a respiratory defect; consistent with this, Rbd1p is localized in the inner mitochondrial membrane and mutant cells have disrupted mitochondria. We have identified two substrates of Rbd1p: cytochrome c peroxidase (Ccp1p); and a dynamin-like GTPase (Mgm1p), which is involved in mitochondrial membrane fusion6,7,8,9,10. Rbd1p mutants are indistinguishable from Mgm1p mutants, indicating that Mgm1p is a key substrate of Rbd1p and explaining the rbd1Δ mitochondrial phenotype. Our data indicate that mitochondrial membrane remodelling is regulated by cleavage of Mgm1p and show that intramembrane proteolysis by rhomboids controls cellular processes other than signalling. In addition, mitochondrial rhomboids are conserved throughout eukaryotes and the mammalian homologue, PARL11, rescues the yeast mutant, suggesting that these proteins represent a functionally conserved subclass of rhomboid proteases.

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Figure 1: Characterization of Rbd1p.
Figure 2: Phenotypes of candidate Rbd1p substrates.
Figure 3: Cleavage of Ccp1p and Mgm1p depends on Rbd1p in vivo.
Figure 4: Mitochondrial rhomboids are conserved in higher eukaryotes.

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Acknowledgements

We thank H. Pelham, S. Munro and J. Whyte for help and support; B. De Strooper for discussions; members of our laboratory for advice; M. Yaffe, R. Jensen and B. Westermann for antibodies; and P. Cliften and M. Johnston for providing yeast sequences before publication. G.A.M. is supported by an EMBO long-term fellowship.

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  1. MRC Laboratory of Molecular Biology, Hills Road, CB2 2QH, Cambridge, UK

    G. Angus McQuibban, Saroj Saurya & Matthew Freeman

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  1. G. Angus McQuibban
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  2. Saroj Saurya
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  3. Matthew Freeman
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Correspondence to Matthew Freeman.

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McQuibban, G., Saurya, S. & Freeman, M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423, 537–541 (2003). https://doi.org/10.1038/nature01633

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