Slipins: ancient origin, duplication and diversification of the stomatin protein family
© Green and Young; licensee BioMed Central Ltd. 2008
Received: 03 August 2007
Accepted: 11 February 2008
Published: 11 February 2008
Stomatin is a membrane protein that was first isolated from human red blood cells. Since then, a number of stomatin-like proteins have been identified in all three domains of life. The conservation among these proteins is remarkable, with bacterial and human homologs sharing 50 % identity. Despite being associated with a variety of diseases such as cancer, kidney failure and anaemia, precise functions of these proteins remain unclear.
We have constructed a comprehensive phylogeny of all 'stomatin-like' sequences that share a 150 amino acid domain. We show these proteins comprise an ancient family that arose early in prokaryotic evolution, and we propose a new nomenclature that reflects their phylogeny, based on the name "slipin" (stomatin-like protein). Within prokaryotes there are two distinct subfamilies that account for the two different origins of the eight eukaryotic stomatin subfamilies, one of which gave rise to eukaryotic SLP-2, renamed here "paraslipin". This was apparently acquired through the mitochondrial endosymbiosis and is widely distributed amongst the major kingdoms. The other prokaryotic subfamily gave rise to the ancestor of the remaining seven eukaryotic subfamilies. The highly diverged "alloslipin" subfamily is represented only by fungal, viral and ciliate sequences. The remaining six subfamilies, collectively termed "slipins", are confined to metazoa. Protostome stomatin, as well as a newly reported arthropod subfamily slipin-4, are restricted to invertebrate groups, whilst slipin-1 (previously SLP-1) is present in nematodes and higher metazoa. In vertebrates, the stomatin family expanded considerably, with at least two duplication events giving rise to podocin and slipin-3 subfamilies (previously SLP-3), with the retained ancestral sequence giving rise to vertebrate stomatin.
Stomatin-like proteins have their origin in an ancient duplication event that occurred early on in the evolution of prokaryotes. By constructing a phylogeny of this family, we have identified and named a number of orthologous groups: these can now be used to infer function of stomatin subfamilies in a meaningful way.
Human stomatin (hstomatin) was first identified as an integral membrane protein in human red blood cells [1–3]. It has since been shown to be expressed in many cell types and organisms, although hstomatin function remains unclear . Loss of stomatin in humans is associated with a condition called overhydrated hereditary stomatocytosis, in which the red blood cells leak Na+ and K+ ions , although the hstomatin gene is not mutated in these patients . Other human proteins showing high similarity to human stomatin (> 50 %) have also been described. Human stomatin-like protein-2 (hSLP-2) is a 39 kDa, widely expressed, oligomeric, peripheral membrane protein that associates with the spectrin-actin cytoskeleton in the red cell . It has recently been shown to be overexpressed in a variety of human tumours , being one of the 16 most upregulated proteins in superinvasive cancer cells, although its function is again unknown . Human stomatin-like protein-3 (hSLP-3), an olfactory neuronal protein , shares 84 % similarity with hstomatin and is important for the function of skin mechanoreceptors in the mouse . Podocin is 73 % similar to hstomatin and, like stomatin, is raft associated . Podocin is expressed exclusively in the kidneys, where it is localised to the membrane of podocytes; these are specialised cells involved in the ultrafiltration of blood . Mutations in the podocin gene (NPHS2) result in nephritic syndrome, in which protein appears in the urine; the end stage of this condition is renal failure . The final member of this putative family is human stomatin-like protein-1 (hSLP-1), which differs from the other stomatin proteins in that it is a bipartite protein that contains a stomatin-like region fused to a non-specific lipid transfer protein .
Stomatin-like proteins are not confined to humans. Work on Caenorhabditis elegans has identified at least nine proteins showing similarity to human stomatin. One of these, UNC-24, is necessary for the movement of another protein from the endoplasmic reticulum to the cell membrane  and has recently been shown to share a common ancestor with hSLP-1 . The apicomplexan parasite Plasmodium falciparum contains a stomatin-like protein that co-localises with invasion-associated rhoptry organelles and is involved in the formation of the invasion vacuole during infection of red blood cells . Of particular interest to us is the prokaryotic group of stomatin-like proteins. These were first identified by You and Borthakur  who showed, through a mutagenesis screen, that a stomatin-like protein was involved in the competitiveness of Rhizobium etli for nodulation of the roots of Phaseolus vulgaris. The widespread distribution of stomatins and their associated diseases strongly suggests that their biological functions are of great importance, yet to date these remain unclear. If we are to understand the function of human stomatins by studying these proteins in other organisms then it is important that we can distinguish sequences that have evolved by speciation (orthologues) from those that have evolved by duplication (paralogues): to achieve this end we need a stomatin family phylogeny. So far, stomatin family evolution has always been considered in the context of a superfamily involving stomatins, prohibitins, flotillins and HflK/C proteins  and plant disease response genes . However, more recently this superfamily concept has been revisited, and is now regarded to have little phylogenetic support . It is therefore likely that similarity among members is a result of convergent evolution and not shared ancestry.
In this paper we have chosen to undertake a phylogenetic analysis of stomatin-like proteins only. Our results reveal an intriguing story of ancient origin, duplication and diversification of stomatin family members and identifies candidate organisms that should be used when attempting to understand stomatin function outside of primate systems.
Two Different Origins of Eukaryotic Stomatins
A selection of stomatin subfamilies.
Capitella sp. I
JGIest_ 32235 (62)
XP_457231.1 (30) Ω
XP_001033024.1 (35) Ω
NP_148418.2 (52) ‡
NP_126340.1 (49) ‡
YP_440000.1 (48) ‡
Paraslipin Subfamily Phylogeny
The lower paraslipin clade contains both bacterial and eukaryotic species. Representatives of the gamma Proteobacteria, Chlorobi and Spirochetes each have two, divergent copies of prokaryotic paraslipin suggesting an early duplication event. A very significant feature of the lower group is the strong support (100 %) for a monophyletic group containing Rickettsiales and eukaryotic paraslipins, with Rickettsiales forming the sister group to the eukaryotic clade. This suggests a possible mitochondrial origin of eukaryotic paraslipins. Within eukaryotes we see a mostly well-resolved phylogeny with many of the major taxonomic groups being recovered as monophyletic. As expected, fungi form the sister group to metazoa with plants and protists falling outside of this Opisthokont clade ; the ecdysozoan group of insects and nematodes is not supported, but neither is it significantly contradicted.
From Figure 1 it was apparent that many stomatin subfamilies arose within the vertebrate lineage. To try to understand the origin and evolution of vertebrate sequences, two separate phylogenies were constructed and are shown in Figure 5. The first phylogeny was based on an alignment of chordate and echinoderm sequences, and this was rooted with slipin-4 and protostome stomatin sequences. Although poorly supported, chordate and protostome sequences form separate groups.
To gain more information about the duplication events that occurred within the vertebrate portion of our tree, a vertebrate-specific phylogeny were constructed that allowed for a longer alignment (Figure 5, shaded box). Stomatin sequences from the echinoderm Strongylocentrotus purpuratus and the urochordate Ciona intestinalis were included so that an approximate time frame for the origin of these subfamilies could be established. The vertebrate-specific phylogeny recovers the same topology as seen if slipin-4 and protostome sequences are included but, in addition, provides strong support (87 %) for the monophyly of vertebrate subfamilies with the Ciona intestinalis sequences forming the sister group. Within vertebrates there are three well-supported monophyletic groups. Podocin proteins form the most basal vertebrate group and are clearly quite divergent from the other subfamilies, as judged by their long branch. The other two clades group stomatin and slipin-3 proteins into two well-resolved clusters. In each case the three clades support congruent phylogenies, although not all vertebrates were found to have all proteins (Table 1). However, recently derived paralogues may be substituting for the function of missing genes.
Our analyses suggest that the stomatin family is a sound concept, with all its members showing high levels of sequence conservation over a region of 150 amino acids. Eukaryotic stomatin proteins have two independent prokaryotic origins: one gave rise to all eukaryotic paraslipin proteins, whilst the other gave rise to the remaining subfamilies (alloslipin, slipin-1, slipin-3, slipin-4, protostome stomatin, stomatin and podocin).
Figure 3 presents strong support for the transfer of paraslipin (lower clade, Figure 3) into eukaryotes from a rickettsia-like proteobacterium. The source could plausibly have been the progenitor of the mitochondrion . This hypothesis is further supported by the observation that paraslipin is present within the rat mitochondrial proteome  and shows a significant decrease in expression in mitochondria devoid of DNA . It is also interesting to note that the only protist species we found not to encode paraslipin were the amitochondriates Giardia lamblia and Trichomonas vaginalis and the distantly related Entamoeba histolytica [30, 31]. Once acquired by eukaryotes, paraslipin evolved with very little gene duplication and became taxonomically widespread (Table 1, Figure 3).
The eukaryotic slipin and alloslipin subfamilies probably evolved from a common ancestor shared by archaea and eukaryotes, to the exclusion of bacteria, although our phylogeny is too poorly resolved at present to support such a hypothesis. The discovery of alloslipins is an important finding in our quest to understand stomatin family phylogeny, as these are the first eukaryotic slipin-like sequences identified outside metazoa. However, despite detailed searches of protist and basal metazoan genomes, we have been unable to resolve the currently bizarre taxonomic distribution of alloslipin proteins. Within metazoa, slipins have been subjected to numerous gene duplication events, and at least one gene fusion event with a sterol carrier protein that occurred prior to the divergence of protostomes and deuterostomes  and gave rise to SLP-1, now named slipin-1. Within protostomes, there are at least two other subfamilies (Figure 4). One of these groups includes arthropods, molluscs, annelids and a nematode, uniting the protostomes into a monophyletic group, which we have named protostome stomatin to reflect the short branches and phylogenetic range. The topology of Figure 5 suggests that slipin-4 and protostome stomatin may in fact be paralogues that arose before ecdysozoans and lophotrochozoans diverged; following this duplication event slipin-4 was lost from most taxa.
Within vertebrates, we see the origin of podocin, slipin-3 and stomatin proteins, and we propose that these arose as a result of two gene duplication events (Figure 7). The inclusion of Danio rerio sequences within all three vertebrate groups suggests both duplication events occurred before the teleost/tetrapod split. The placement of the sea squirt sequences as the sister group to this clade dates the time of divergence to after the chordate/urochordate divergence. If we accept the loss of a paralogue, this phylogeny supports the two whole genome duplication events that are proposed to have occurred prior to the origin of vertebrates [32, 33], accounting for the origin of slipin-3, podocin and stomatin. Whilst there appears to have been little sequence divergence in vertebrate stomatin sequences, podocin and, to a lesser extent, slipin-3 have undergone significant sequence evolution (Figures 5 and 6) making it likely that they are functioning in a distinctly different manner to other family members.
The goal of this study was to provide a conceptual framework within which to study this family. This can be used to improve understanding of stomatin function in humans and to identify relevant homologs to investigate subfamily function. Whilst it is likely that slipin-3, podocin and alloslipin proteins are functioning in new ways (as judged by the long branches leading to these groups), it is not clear whether hstomatin has retained its ancestral function. The lack of any significant divergence within this clade, the conservation of protein length and the sequence conservation, all suggest that vertebrate stomatin may indeed be functioning in a similar way to protostome stomatin and possibly eoslipin. The conservation of motifs (Figure 6) suggests a shared mechanism among these subfamilies, although the downstream effects might be very different. The placement of Rickettsiales as the sister group to eukaryotic paraslipins (Figure 3) suggests that alphaproteobacteria may serve as a relevant system to investigate human paraslipin function.
It seems clear that the stomatin-like proteins have their origin in an ancient duplication event that occurred early on in the evolution of prokaryotes. A high degree of conservation implies that they have important functions, though these remain almost completely unknown. By constructing a phylogeny of this family, we have identified and named a number of orthologous groups. Investigation of many different organisms could potentially contribute to an understanding of stomatin-like proteins, and we hope that our analysis will make it easier to describe and interpret such studies.
The human stomatin amino acid sequence [NCBI:NP_004090.4] was used to search the National Centre for Biotechnology Information (NCBI) non-redundant (nr) database using BLASTP with default settings . The query was restricted to eukaryotes as organisms. To identify prokaryotic stomatin-like proteins, the human stomatin and SLP-2 amino acid sequences were used to search the NCBI nr bacterial and archaeal databases. Sequences with an E-value of < 10-14 were retrieved in FASTA format and saved. Blasting with human stomatin was sufficient to retrieve all stomatin, podocin and SLP-3 proteins. SLP-1 proteins were not retrieved as the presence of the sterol carrier domain limits the alignment length (for a review of SLP-1 phylogeny see Edqvist and Blomqvist 2006). To further explore the distribution of slipins and paraslipins in key eukaryotic genomes, BLASTP and tBLASTn searches were performed against the eukaryotic genomes of the Joint Genome Institute (JGI) using both human stomatin and Tetrahymena thermophila [NCBI:XP_001033024.1] alloslipin sequences with default settings.
Protein Alignment and Phylogenetic Analysis
Retrieved sequences were checked by aligning them with their query sequence using ClustalX 1.83  with the following parameters: gap penalty = 10, gap extension penalty = 0.10. The Gonnet series protein weight matrix was used in the ClustalX alignment. Sequences that failed to align or contained significant gaps (> 50 aa) were deleted. Checked sequences were re-aligned using ClustalX and a preliminary distance Neighbour Joining (NJ) tree  was produced for prokaryotic and eukaryotic proteins to determine the number and composition of subgroups, with 1000 bootstrap pseudoreplicates performed. From this initial tree, sequences from well supported monophyletic groups were selected for the various phylogenetic analyses, realigned and edited using BioEdit  to remove any ambiguously aligned positions. Where organisms contained multiple copies of the same protein, the protein with the best BLAST score to the search query was chosen. To limit the problems associated with long branch attraction, we removed divergent species-specific paralogues that failed to form orthologous groups. The resulting alignment was then used to construct a NJ tree (ClustalX 1.83, n = 1000) and a maximum likelihood (ML) phylogenetic tree using PHYML . For ML analysis the JTT substitution matrix was used for calculation of the amino acid substitutions . A discrete-gamma distribution with four categories was used to account for variable substitution rates among sites. The gamma distribution parameter was estimated by PHYML. A BIONJ distance tree was used as the starting tree to be refined by the maximum likelihood algorithm. The robustness of the tree was determined by bootstrapping using 100 repetitions. Various subgroups were then selected and used to build further maximum likelihood trees as described above. All trees were displayed using NJ plot  except Figure 1 which was viewed using TreeView .
Generation of Consensus Sequences
Sequences from monophyletic groups identified by ML analysis were aligned using ClustalX. BioEdit was then used to create a 70–100 % consensus sequence for each group depending on the number of taxa. X was used to represent a non-consensus position. Consensus sequences were then aligned using ClustalX with default settings and viewed using BOXSHADE  with the identity shading threshold set at 0.6.
JBG thanks Professor Gordon Stewart for introducing him to this fascinating protein family. We thank Xavier Bailly (funded by NERC) for useful discussions and comments on this manuscript. This work was supported by a BBSRC studentship to JBG, supervised by JPWY.
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