SmlA (small aggregate formation protein) is a cytosolic protein of Dictyostelium discoideum that regulates the size of the multicellular aggregates formed by starving cells. It is expressed in vegetative and early developing cells, with mRNA declining after about 10 hours of development. SmlA itself is not secreted and has no recognizable sequence motifs; instead it acts intracellularly to restrain the secretion (or processing) of counting factor (CF), a secreted multisubunit complex (including countin) that provides negative feedback limiting group size. Loss of SmlA causes oversecretion of counting factor, so that aggregation streams break up excessively and cells form large numbers of small aggregates and fruiting bodies. Downstream of this pathway, counting factor lowers intracellular glucose by inhibiting glucose-6-phosphatase, so smlA-null cells (with high CF activity) show altered glucose-6-phosphatase activity and glucose metabolism. SmlA is thus a size-control regulator acting upstream of the secreted counting-factor signalling system rather than an enzyme with a defined catalytic activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: SmlA is a cytosolic protein, directly demonstrated by immunofluorescence and cell fractionation. The general cytoplasm term is correct and consistent with the more specific cytosol annotation. Reason: Direct experimental evidence establishes SmlA as a cytosolic protein, so this UniProt-derived cytoplasm annotation is well supported. Supporting Evidence: PMID:8787732 SmlA is a 35x10(3) Mr cytosolic protein present in all vegetative and developing cells |
| GO:0031157 regulation of aggregate size involved in sorocarp development | IEA GO_REF:0000002 | ACCEPT | Summary: This InterPro2GO annotation (from the SmlA-specific InterPro signature) captures the core, defining biological role of SmlA, which was discovered as a gene controlling aggregate size. It is correct and central to SmlA function. Reason: SmlA was identified precisely because its loss changes aggregate size, and the InterPro-to-GO mapping to regulation of aggregate size is consistent with the primary experimental literature. This is a core process annotation. Supporting Evidence: PMID:8787732 the cytosolic protein SmlA regulates the secretion or processing of a secreted factor that regulates aggregate size |
| GO:0051156 glucose 6-phosphate metabolic process | IMP PMID:16606621 A protein in crude cytosol regulates glucose-6-phosphatase a... | KEEP AS NON CORE | Summary: smlA-null cells (which oversecrete counting factor) show altered microsome-associated glucose-6-phosphatase activity. This links SmlA to glucose-6-phosphate metabolism, but only indirectly and downstream of the counting-factor size-control pathway rather than as a core function. Reason: The effect on glucose-6-phosphate metabolism is a downstream consequence of the counting-factor pathway that SmlA modulates, not a direct molecular activity of SmlA. It is a genuine phenotype but peripheral to the core size-regulation role. Supporting Evidence: PMID:16606621 CF regulates one or more proteins greater than 10 KDa in crude cytosol that affect microsome-associated glucose-6-phosphatase activity |
| GO:0031159 positive regulation of aggregate size involved in sorocarp development | IGI PMID:17660362 A cell number-counting factor regulates levels of a novel pr... | ACCEPT | Summary: Loss of SmlA causes formation of small groups due to oversecretion of counting factor, so SmlA normally acts to promote larger aggregate/group size. A genetic interaction with sslA (a second-site suppressor of smlA-null) supports SmlA acting within the group-size regulation pathway. Reason: The direction is well established - smlA loss reduces group size, so SmlA positively regulates aggregate size. The genetic interaction with sslA places SmlA in the counting-factor size-control pathway. This is a core process for the gene. Supporting Evidence: PMID:17660362 a transformant that forms small groups due to oversecretion of CF |
| GO:0045335 phagocytic vesicle | HDA PMID:19482547 Proteomic analysis of Legionella-containing phagosomes isola... | MARK AS OVER ANNOTATED | Summary: SmlA was detected among 157 proteins in a high-throughput proteomic catalog of Legionella-containing phagosomes. This is an incidental mass- spectrometry hit that conflicts with the well-established cytosolic localization of SmlA and does not reflect a functional phagosomal role. Reason: High-throughput phagosome proteomics readily captures abundant cytosolic proteins as contaminants. SmlA is directly shown to be cytosolic, so a phagocytic-vesicle location is an over-annotation of a large-scale dataset rather than a functional localization. Supporting Evidence: PMID:19482547 identified 157 phagosome host proteins |
| GO:0006974 DNA damage response | IMP PMID:17878305 Global transcriptional responses to cisplatin in Dictyosteli... | MARK AS OVER ANNOTATED | Summary: smlA was one of five genes whose mutation altered cisplatin sensitivity in a transcriptional-profiling drug-target screen. The same paper notes that smlA participates in aggregate size regulation. Mapping an altered drug-sensitivity phenotype to DNA damage response over-interprets SmlA's role. Reason: The evidence is an altered cisplatin sensitivity phenotype, not a demonstrated role in the molecular response to DNA damage. SmlA has no known DNA-repair or damage-signalling activity, and the authors attribute its characterized function to aggregate size regulation. This term over-annotates an indirect drug-sensitivity readout. Supporting Evidence: PMID:17878305 Mutations in five cisplatin response genes ( sgkB , csbA , acbA , smlA , and atg8 ) resulted in altered drug sensitivity PMID:17878305 smlA participate in aggregate size regulation |
| GO:0031159 positive regulation of aggregate size involved in sorocarp development | TAS PMID:15366765 Comparison of molecular mechanisms mediating cell contact ph... | ACCEPT | Summary: This TAS annotation from a broad review assigns the same core group- size regulation role that is directly supported by the primary literature. The term is correct, though the reference is a general review rather than a primary study of SmlA. Reason: The positive regulation of aggregate size role is well established from the primary experimental work (loss of SmlA yields small aggregates). The annotation term is correct and represents a core function. Supporting Evidence: PMID:8787732 causes starved cells to form large numbers of small aggregates |
| GO:0005576 extracellular region | IDA PMID:8787732 A Dictystelium mutant with defective aggregate size determin... | REMOVE | Summary: The primary reference explicitly states that no SmlA protein is detectably secreted and that SmlA is cytosolic. An extracellular-region location therefore contradicts the direct evidence in the same paper. Reason: SmlA acts intracellularly to regulate secretion of a distinct secreted factor; it is not itself secreted. The extracellular annotation is directly contradicted by the cited study, which reports no detectable secreted SmlA and a cytosolic localization. Supporting Evidence: PMID:8787732 Although there is no detectable SmlA protein secreted from cells PMID:8787732 SmlA is a 35x10(3) Mr cytosolic protein present in all vegetative and developing cells |
| GO:0042593 glucose homeostasis | IMP PMID:15643062 Exposure of cells to a cell number-counting factor decreases... | KEEP AS NON CORE | Summary: Counting factor, whose secretion SmlA restrains, lowers intracellular glucose by inhibiting glucose-6-phosphatase. Thus smlA-null cells show altered glucose metabolism, but this is a downstream consequence of the size-control pathway rather than a core SmlA function. Reason: The glucose-homeostasis phenotype reflects the downstream metabolic arm of the counting-factor pathway that SmlA modulates. It is a real but peripheral effect, not a direct molecular role of SmlA. Supporting Evidence: PMID:15643062 part of the CF signal transduction pathway involves inhibiting the activity of glucose-6-phosphatase, decreasing intracellular glucose levels and affecting the levels of other metabolites, to regulate group size |
| GO:0050708 regulation of protein secretion | IMP PMID:8787732 A Dictystelium mutant with defective aggregate size determin... | MODIFY | Summary: SmlA controls the secretion (or processing) of the secreted counting factor that limits aggregate size; loss of SmlA leads to oversecretion of this factor. The generic regulation-of-secretion term is correct, but the direction is now known - SmlA restrains secretion - so a negative-regulation term is more informative. Reason: The core molecular-level role of SmlA is to limit secretion of counting factor (smlA-null cells oversecrete CF). Replacing the direction-neutral term with negative regulation of protein secretion better captures the demonstrated function. Proposed replacements: negative regulation of protein secretion Supporting Evidence: PMID:8787732 the cytosolic protein SmlA regulates the secretion or processing of a secreted factor that regulates aggregate size PMID:17660362 a transformant that forms small groups due to oversecretion of CF |
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: No molecular function has been determined for SmlA. The protein has no recognizable motifs or sequence similarity that would indicate an activity, consistent with the root ND annotation. Reason: The molecular function of SmlA is genuinely unknown; the ND placeholder is appropriate given the absence of identifiable functional motifs. Supporting Evidence: PMID:8787732 The sequence of the cDNA and the derived amino acid sequence of the SmlA protein show no significant similarity to any known sequence. |
| GO:0005829 cytosol | IDA PMID:8787732 A Dictystelium mutant with defective aggregate size determin... | ACCEPT | Summary: Direct experimental evidence (immunofluorescence and Western blotting of cell fractions) shows SmlA is a cytosolic protein. This is the correct and core subcellular localization. Reason: SmlA is directly demonstrated to be cytosolic, and it acts intracellularly to regulate secretion of counting factor. This is a core localization annotation. Supporting Evidence: PMID:8787732 SmlA is a 35x10(3) Mr cytosolic protein present in all vegetative and developing cells |
| GO:0007165 signal transduction | IMP PMID:8787732 A Dictystelium mutant with defective aggregate size determin... | KEEP AS NON CORE | Summary: SmlA acts within the counting-factor negative-feedback signalling system that regulates group size. The generic signal transduction term is correct but far less informative than the specific aggregate-size regulation and secretion-control terms already annotated. Reason: SmlA operates within a secreted-signal (counting factor) size-control pathway, so a signal-transduction annotation is defensible, but it is too general to represent the core function, which is better captured by the aggregate-size regulation and negative-regulation-of-secretion terms. Supporting Evidence: PMID:8787732 the cytosolic protein SmlA regulates the secretion or processing of a secreted factor that regulates aggregate size |
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Download this section (compressed HTML)Q: What is the molecular activity of SmlA, given that it carries no recognizable catalytic or binding domain yet negatively controls counting-factor secretion?
Experiment: In wild-type versus smlA-null cells, compare counting-factor (e.g. countin) mRNA and intracellular protein against the amount of secreted, active counting factor, and identify SmlA interaction partners by co-immunoprecipitation to place SmlA on the secretory or processing pathway.
Hypothesis: SmlA limits counting factor at the level of secretion or processing rather than at the level of transcription.
Type: comparative expression and interactome analysis
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