Abstract
BackgroundPhosphorylated phosphatidylinositol (PtdIns) lipids, produced and modified by PtdIns kinases and phosphatases, are critical to the regulation of diverse cellular functions. The myotubularin PtdIns-phosphate phosphatases have been well characterized in yeast and especially animals, where multiple isoforms, both catalytically active and inactive, occur. Myotubularin mutations bring about disruption of cellular membrane trafficking, and in humans, disease. Previous studies have suggested that myotubularins are widely distributed amongst eukaryotes, but key evolutionary questions concerning the origin of different myotubularin isoforms remain unanswered, and little is known about the function of these proteins in most organisms.ResultsWe have identified 80 myotubularin homologues amidst the completely sequenced genomes of 30 organisms spanning four eukaryotic supergroups. We have mapped domain architecture, and inferred evolutionary histories. We have documented an expansion in the Amoebozoa of a family of inactive myotubularins with a novel domain architecture, which we dub "IMLRK" (inactive myotubularin/LRR/ROCO/kinase). There is an especially large myotubularin gene family in the pathogen Entamoeba histolytica, the majority of them IMLRK proteins. We have analyzed published patterns of gene expression in this organism which indicate that myotubularins may be important to critical life cycle stage transitions and host infection.ConclusionsThis study presents an overall framework of eukaryotic myotubularin gene evolution. Inactive myotubularin homologues with distinct domain architectures appear to have arisen on three separate occasions in different eukaryotic lineages. The large and distinctive set of myotubularin genes found in an important pathogen species suggest that in this organism myotubularins might present important new targets for basic research and perhaps novel therapeutic strategies.
Highlights
Phosphorylated phosphatidylinositol (PtdIns) lipids, produced and modified by PtdIns kinases and phosphatases, are critical to the regulation of diverse cellular functions
We found that myotubularin genes are nearly ubiquitous in eukaryotes, being readily identifiable in all the major eukaryotic groups and in all genomes examined with the notable exception of the obligate intracellular parasites Encephalitozoon cuniculi (Microsporidia) and Plasmodium falciparum (Apicomplexa) and eukaryotic algae, both red (Cyanidioschyzon merolae) and green (Ostreococcus sp., Chlamydomonas reinhardtii)
We have presented a phylogenetic survey of myotubularin genes across a diverse array of eukaryotes, including distribution, domain architecture, and inferred evolutionary history
Summary
Phosphorylated phosphatidylinositol (PtdIns) lipids, produced and modified by PtdIns kinases and phosphatases, are critical to the regulation of diverse cellular functions. The myotubularin PtdIns-phosphate phosphatases have been well characterized in yeast and especially animals, where multiple isoforms, both catalytically active and inactive, occur. Myotubularin mutations bring about disruption of cellular membrane trafficking, and in humans, disease. Phosphatidylinositol (PtdIns) phospholipids are quantitatively minor but functionally significant membrane lipid components which have been shown to be involved in regulating diverse aspects of cellular function, such as proliferation, survival, growth, cytoskeletal reorganization, and various membrane trafficking events. There is a large myotubularin family in humans (14 genes) which encode both catalytically active and inactive members. Mutations in either active or inactive members of this family bring about human disease, which involves skeletal muscle (X-linked myotubular myopathy [XLMTM]) or peripheral neurons (Charcot-Marie-Tooth [CMT] neuropathies) [2,3,4]. Previous phylogenetic studies have reported the presence of myotubularin genes in plants, fungi and some protists, with the latter group only containing both active and inactive forms [2,5]
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