smlA

id: P54661
gene_symbol: smlA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: 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.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Direct experimental evidence establishes SmlA as a cytosolic protein,
      so this UniProt-derived cytoplasm annotation is well supported.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: SmlA is a 35x10(3) Mr cytosolic protein present in all
        vegetative and developing cells
- term:
    id: GO:0031157
    label: regulation of aggregate size involved in sorocarp development
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: the cytosolic protein SmlA regulates the secretion or
        processing of a secreted factor that regulates aggregate size
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IMP
  original_reference_id: PMID:16606621
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16606621
      supporting_text: CF regulates one or more proteins greater than 10 KDa in
        crude cytosol that affect microsome-associated glucose-6-phosphatase activity
- term:
    id: GO:0031159
    label: positive regulation of aggregate size involved in sorocarp development
  evidence_type: IGI
  original_reference_id: PMID:17660362
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17660362
      supporting_text: a transformant that forms small groups due to oversecretion
        of CF
- term:
    id: GO:0045335
    label: phagocytic vesicle
  evidence_type: HDA
  original_reference_id: PMID:19482547
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19482547
      supporting_text: identified 157 phagosome host proteins
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IMP
  original_reference_id: PMID:17878305
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17878305
      supporting_text: Mutations in five cisplatin response genes ( sgkB , csbA ,
        acbA , smlA , and atg8 ) resulted in altered drug sensitivity
    - reference_id: PMID:17878305
      supporting_text: smlA participate in aggregate size regulation
- term:
    id: GO:0031159
    label: positive regulation of aggregate size involved in sorocarp development
  evidence_type: TAS
  original_reference_id: PMID:15366765
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: causes starved cells to form large numbers of small
        aggregates
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:8787732
  qualifier: colocalizes_with
  review:
    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.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: Although there is no detectable SmlA protein secreted from
        cells
    - reference_id: PMID:8787732
      supporting_text: SmlA is a 35x10(3) Mr cytosolic protein present in all
        vegetative and developing cells
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:15643062
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:15643062
      supporting_text: 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
- term:
    id: GO:0050708
    label: regulation of protein secretion
  evidence_type: IMP
  original_reference_id: PMID:8787732
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0050709
      label: negative regulation of protein secretion
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: the cytosolic protein SmlA regulates the secretion or
        processing of a secreted factor that regulates aggregate size
    - reference_id: PMID:17660362
      supporting_text: a transformant that forms small groups due to oversecretion
        of CF
- term:
    id: GO:0003674
    label: molecular_function
  evidence_type: ND
  original_reference_id: GO_REF:0000015
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: The molecular function of SmlA is genuinely unknown; the ND placeholder
      is appropriate given the absence of identifiable functional motifs.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: The sequence of the cDNA and the derived amino acid sequence
        of the SmlA protein show no significant similarity to any known sequence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:8787732
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: SmlA is directly demonstrated to be cytosolic, and it acts
      intracellularly to regulate secretion of counting factor. This is a core
      localization annotation.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: SmlA is a 35x10(3) Mr cytosolic protein present in all
        vegetative and developing cells
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IMP
  original_reference_id: PMID:8787732
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:8787732
      supporting_text: the cytosolic protein SmlA regulates the secretion or
        processing of a secreted factor that regulates aggregate size
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000015
  title: Use of the ND evidence code for Gene Ontology (GO) terms
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:15366765
  title: 'Comparison of molecular mechanisms mediating cell contact phenomena in model
    developmental systems: an exploration of universality.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Broad review of cell-contact mechanisms across model systems; the
      abstract does not discuss SmlA specifically. The TAS annotation to positive
      regulation of aggregate size is correct on the biology but the primary support
      comes from the Brock/Gomer studies.
- id: PMID:15643062
  title: Exposure of cells to a cell number-counting factor decreases the activity
    of glucose-6-phosphatase to decrease intracellular glucose levels in Dictyostelium
    discoideum.
  findings:
  - statement: Counting factor signal transduction inhibits glucose-6-phosphatase to
      decrease intracellular glucose and regulate group size, the downstream metabolic
      arm of the pathway that SmlA modulates.
    supporting_text: 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
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the CF-glucose-6-phosphatase-glucose axis downstream of
      the size-control pathway; SmlA is upstream via its control of CF secretion.
- id: PMID:16606621
  title: A protein in crude cytosol regulates glucose-6-phosphatase activity in crude
    microsomes to regulate group size in Dictyostelium.
  findings:
  - statement: A counting-factor-regulated cytosolic protein activity modulates
      microsome-associated glucose-6-phosphatase to regulate group size; smlA-null
      cells are used as a high-CF background in these assays.
    supporting_text: CF regulates one or more proteins greater than 10 KDa in crude
      cytosol that affect microsome-associated glucose-6-phosphatase activity
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Links the counting-factor pathway to glucose-6-phosphatase
      regulation; relevant to the glucose-6-phosphate/glucose-homeostasis annotations
      on smlA as downstream, non-core effects.
- id: PMID:17660362
  title: A cell number-counting factor regulates levels of a novel protein, SslA,
    as part of a group size regulation mechanism in Dictyostelium.
  findings:
  - statement: smlA-null cells form small groups because they oversecrete counting
      factor; SslA was isolated as a second-site suppressor, placing SmlA in the
      counting-factor group-size pathway.
    supporting_text: a transformant that forms small groups due to oversecretion of CF
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Directly ties smlA loss to counting-factor oversecretion and small
      group size, and provides the genetic interaction (sslA) supporting the IGI
      annotation.
- id: PMID:17878305
  title: Global transcriptional responses to cisplatin in Dictyostelium discoideum
    identify potential drug targets.
  findings:
  - statement: smlA mutation alters cisplatin sensitivity in a drug-target screen,
      while the paper attributes SmlA's characterized function to aggregate size
      regulation.
    supporting_text: smlA participate in aggregate size regulation
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cisplatin sensitivity is an indirect phenotype; it does not support
      a direct DNA damage response function for SmlA.
- id: PMID:19482547
  title: Proteomic analysis of Legionella-containing phagosomes isolated from Dictyostelium.
  findings:
  - statement: SmlA appears in a large-scale phagosome proteome (157 proteins), an
      incidental detection inconsistent with its cytosolic localization.
    supporting_text: identified 157 phagosome host proteins
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput phagosome proteomics catalog; the phagocytic-vesicle
      annotation is an over-annotation for a cytosolic protein.
- id: PMID:8787732
  title: A Dictystelium mutant with defective aggregate size determination.
  findings:
  - statement: SmlA is a cytosolic protein present in vegetative and early developing
      cells.
    supporting_text: SmlA is a 35x10(3) Mr cytosolic protein present in all vegetative
      and developing cells
  - statement: SmlA regulates the secretion or processing of a secreted factor that
      controls aggregate size.
    supporting_text: the cytosolic protein SmlA regulates the secretion or processing
      of a secreted factor that regulates aggregate size
  - statement: SmlA itself is not detectably secreted.
    supporting_text: Although there is no detectable SmlA protein secreted from cells
  - statement: SmlA has no significant sequence similarity to known proteins,
      consistent with an undetermined molecular function.
    supporting_text: The sequence of the cDNA and the derived amino acid sequence of
      the SmlA protein show no significant similarity to any known sequence.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary discovery and characterization of smlA; establishes the
      cytosolic localization, non-secretion, undetermined molecular function, and
      the secretion-control/aggregate-size role.
suggested_questions:
- question: >-
    What is the molecular activity of SmlA, given that it carries no recognizable
    catalytic or binding domain yet negatively controls counting-factor secretion?
suggested_experiments:
- hypothesis: >-
    SmlA limits counting factor at the level of secretion or processing rather
    than at the level of transcription.
  description: >-
    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.
  experiment_type: comparative expression and interactome analysis
core_functions:
- description: SmlA is a cytosolic regulator that restrains the secretion (or
    processing) of counting factor, a secreted multisubunit complex that provides
    negative feedback on group size. By limiting counting-factor secretion, SmlA
    promotes formation of normal, larger aggregates during sorocarp development;
    loss of SmlA causes counting-factor oversecretion, excessive stream breakup,
    and many small fruiting bodies. No catalytic molecular function has been
    identified for SmlA.
  supported_by:
  - reference_id: PMID:8787732
    supporting_text: the cytosolic protein SmlA regulates the secretion or processing
      of a secreted factor that regulates aggregate size
  - reference_id: PMID:17660362
    supporting_text: a transformant that forms small groups due to oversecretion of CF
  directly_involved_in:
  - id: GO:0050709
    label: negative regulation of protein secretion
  - id: GO:0031159
    label: positive regulation of aggregate size involved in sorocarp development
  locations:
  - id: GO:0005829
    label: cytosol