CSH3

id: A0A1D8PLU5
gene_symbol: CSH3
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:237561
  label: Candida albicans (strain SC5314 / ATCC MYA-2876)
description: >-
  ER membrane packaging chaperone in Candida albicans. CSH3 is a functional and
  structural homolog of S. cerevisiae Shr3p, an ER-resident membrane protein
  with 4 transmembrane helices and the SHR3_chaperone Pfam domain (PF08229).
  CSH3/Shr3p is specifically required for proper folding and ER exit of amino
  acid permeases. A csh3-delta/csh3-delta null mutant has reduced amino acid
  uptake capacity and is unable to switch morphologies in response to inducing
  amino acids (PMID:14756779). CSH3 haploinsufficiency impairs amino acid uptake
  and virulence in a mouse model. CSH3 is not a small heat shock protein or
  general unfolded protein binder; it is a specialized ER membrane chaperone for
  amino acid transporter biogenesis.
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER membrane localization. CSH3 is an integral ER
      membrane protein with 4 transmembrane helices, consistent with its
      S. cerevisiae Shr3p ortholog.
    action: ACCEPT
    reason: >-
      ER membrane localization is a core feature of CSH3. The protein has 4
      predicted transmembrane helices (UniProt) and the SHR3_chaperone domain.
      PMID:14756779 demonstrates ER localization by IDA. The IBA annotation
      is well supported.
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER-to-Golgi transport. CSH3/Shr3p assists amino acid
      permeases in proper folding so they can be packaged into COPII vesicles
      for ER-to-Golgi transport.
    action: ACCEPT
    reason: >-
      ER-to-Golgi transport is a direct consequence of CSH3's core function
      as a packaging chaperone. Shr3p is specifically required for proper
      folding of amino acid permeases so they can exit the ER via COPII
      vesicles. This is well established for the Shr3 family and CSH3 is
      a functional ortholog (PMID:14756779).
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for unfolded protein binding. GO:0051082 is proposed for
      obsoletion. CSH3 is not a general unfolded protein binder; it is a
      specialized ER membrane chaperone for amino acid permeases.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. CSH3/Shr3p is an ER membrane packaging
      chaperone that specifically assists in the folding of amino acid permeases
      in the ER membrane. It does not broadly bind unfolded proteins. The
      appropriate replacement is GO:0044183 "protein folding chaperone" which
      captures the chaperone function of assisting protein folding. Note that
      GO:0140309 "unfolded protein carrier activity" would not be appropriate
      because CSH3/Shr3p does not carry/escort proteins between compartments;
      rather, it assists in folding within the ER membrane.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IDA annotation for ER localization from the key characterization paper.
    action: ACCEPT
    reason: >-
      ER localization is directly demonstrated. CSH3 is an integral ER membrane
      protein. PMID:14756779 is the key paper characterizing CSH3 as a
      functional homolog of Shr3p in C. albicans.
    supported_by:
    - reference_id: PMID:14756779
      supporting_text: >-
        The Candida albicans CSH3 gene encodes a functional and structural
        homologue of Shr3p, a yeast protein that is specifically required for
        proper uptake and sensing of extracellular amino acids in Saccharomyces
        cerevisiae.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:19824013
  review:
    summary: >-
      IDA annotation for plasma membrane localization from PMID:19824013.
    action: UNDECIDED
    reason: >-
      Unable to access PMID:19824013 to evaluate the plasma membrane
      localization claim. CSH3/Shr3p is primarily an ER-resident protein,
      so plasma membrane localization would be unexpected. Cannot assess
      without reviewing the publication.
- term:
    id: GO:0030447
    label: filamentous growth
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for filamentous growth. csh3-delta mutants are unable
      to switch morphologies on solid and liquid media.
    action: KEEP_AS_NON_CORE
    reason: >-
      Filamentous growth defect is a downstream phenotypic consequence of
      impaired amino acid sensing/uptake due to loss of CSH3 function. The
      paper shows the csh3-delta/csh3-delta null mutant "is unable to switch
      morphologies on solid and in liquid media in response to inducing amino
      acids" (PMID:14756779). This is not a direct molecular function of CSH3
      but a consequence of its role in amino acid permease biogenesis.
    supported_by:
    - reference_id: PMID:14756779
      supporting_text: >-
        A Candida csh3delta/csh3delta null mutant has a reduced capacity to
        take up amino acids, and is unable to switch morphologies on solid
        and in liquid media in response to inducing amino acids
- term:
    id: GO:0031669
    label: cellular response to nutrient levels
  evidence_type: IMP
  original_reference_id: PMID:16227594
  review:
    summary: >-
      IMP annotation for cellular response to nutrient levels from
      PMID:16227594.
    action: UNDECIDED
    reason: >-
      Unable to access PMID:16227594 to evaluate this annotation. Nutrient
      response involvement is plausible given CSH3's role in amino acid
      uptake, but cannot verify without the publication.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for heat response from the CSH3 characterization paper.
    action: KEEP_AS_NON_CORE
    reason: >-
      Heat response is likely a downstream phenotypic consequence of
      impaired amino acid permease folding. The csh3-delta mutant may show
      heat sensitivity due to general ER stress from misfolded membrane
      proteins. Not a core function.
- term:
    id: GO:0036168
    label: filamentous growth of a population of unicellular organisms in response
      to heat
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for heat-induced filamentous growth from the CSH3
      characterization paper.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a specific manifestation of the morphological switching defect
      of csh3-delta mutants. The inability to undergo filamentous growth in
      response to heat is a downstream consequence of impaired amino acid
      sensing/uptake. Not a core function.
- term:
    id: GO:0036178
    label: filamentous growth of a population of unicellular organisms in response
      to neutral pH
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for pH-induced filamentous growth.
    action: KEEP_AS_NON_CORE
    reason: >-
      Another specific condition under which csh3-delta mutants fail to
      undergo morphological switching. Downstream consequence of amino acid
      permease biogenesis defect. Not a core function.
- term:
    id: GO:0036180
    label: filamentous growth of a population of unicellular organisms in response
      to biotic stimulus
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for biotic stimulus-induced filamentous growth.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same rationale as other filamentous growth annotations -- downstream
      phenotypic consequence of impaired amino acid permease biogenesis.
      Not a core function.
- term:
    id: GO:0036187
    label: cell growth mode switching, budding to filamentous
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for budding-to-filamentous growth switching.
    action: KEEP_AS_NON_CORE
    reason: >-
      Morphological switching defect is a downstream consequence of CSH3's
      role in amino acid permease biogenesis. Not a core function.
    supported_by:
    - reference_id: PMID:14756779
      supporting_text: >-
        A Candida csh3delta/csh3delta null mutant has a reduced capacity to
        take up amino acids, and is unable to switch morphologies on solid
        and in liquid media in response to inducing amino acids.
- term:
    id: GO:0036244
    label: cellular response to neutral pH
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for response to neutral pH.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream phenotypic effect of impaired amino acid permease
      biogenesis. Not a core function.
- term:
    id: GO:0043090
    label: amino acid import
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for amino acid import. The csh3-delta mutant has reduced
      amino acid uptake capacity.
    action: ACCEPT
    reason: >-
      Amino acid import is directly affected by loss of CSH3 function because
      CSH3 is required for proper folding and ER exit of amino acid permeases.
      This is a well-established, direct consequence of the core chaperone
      function and is the key phenotype described in PMID:14756779.
    supported_by:
    - reference_id: PMID:14756779
      supporting_text: >-
        A Candida csh3delta/csh3delta null mutant has a reduced capacity to
        take up amino acids, and is unable to switch morphologies on solid
        and in liquid media in response to inducing amino acids
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: ISS
  original_reference_id: PMID:14756779
  review:
    summary: >-
      ISS annotation for unfolded protein binding by sequence similarity to
      S. cerevisiae Shr3p. GO:0051082 is proposed for obsoletion.
    action: MODIFY
    reason: >-
      Same rationale as the IBA annotation. GO:0051082 is being obsoleted.
      CSH3/Shr3p is a specialized ER membrane chaperone for amino acid
      permeases, not a general unfolded protein binder. Replace with
      GO:0044183 "protein folding chaperone."
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IGI
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IGI annotation for unfolded protein binding based on genetic interaction
      with S. cerevisiae SHR3. GO:0051082 is proposed for obsoletion.
    action: MODIFY
    reason: >-
      Same rationale as the IBA and ISS annotations. GO:0051082 is being
      obsoleted. Replace with GO:0044183 "protein folding chaperone." The
      genetic interaction evidence supports the role of CSH3 as a protein
      folding chaperone for amino acid permeases.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
- term:
    id: GO:1900436
    label: positive regulation of filamentous growth of a population of unicellular
      organisms in response to starvation
  evidence_type: IMP
  original_reference_id: PMID:14756779
  review:
    summary: >-
      IMP annotation for positive regulation of starvation-induced filamentous
      growth.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream phenotypic consequence of impaired amino acid
      sensing/uptake due to loss of CSH3 function. Not a core molecular
      function.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:14756779
  title: An ER packaging chaperone determines the amino acid uptake capacity and virulence
    of Candida albicans.
  findings:
  - statement: >-
      CSH3 is a functional and structural homolog of S. cerevisiae Shr3p.
    supporting_text: >-
      The Candida albicans CSH3 gene encodes a functional and structural
      homologue of Shr3p, a yeast protein that is specifically required for
      proper uptake and sensing of extracellular amino acids in Saccharomyces
      cerevisiae.
  - statement: >-
      csh3-delta mutant has reduced amino acid uptake and impaired
      morphological switching.
    supporting_text: >-
      A Candida csh3delta/csh3delta null mutant has a reduced capacity to
      take up amino acids, and is unable to switch morphologies on solid
      and in liquid media in response to inducing amino acids.
  - statement: >-
      CSH3 haploinsufficiency affects virulence in mouse model.
    supporting_text: >-
      both CSH3/csh3delta heterozygous and csh3delta/csh3delta homozygous
      strains are unable to efficiently mount virulent infections in a mouse
      model.
- id: PMID:16227594
  title: Divergence of Stp1 and Stp2 transcription factors in Candida albicans
    places virulence factors required for proper nutrient acquisition under amino
    acid control.
  findings: []
- id: PMID:19824013
  title: Analysis of Candida albicans plasma membrane proteome.
  findings: []
core_functions:
- description: >-
    ER membrane packaging chaperone that specifically assists in the folding
    and ER exit of amino acid permeases. Required for proper amino acid uptake
    capacity and, consequently, for amino acid-induced morphological switching
    and virulence.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  - id: GO:0043090
    label: amino acid import
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane