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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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. |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IBA GO_REF:0000033 | ACCEPT | 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. 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). Supporting Evidence: file:CANAL/CSH3/CSH3-deep-research-falcon.md Shr3-family proteins are specialized ER membrane chaperones that are required for efficient ER exit and plasma membrane localization of a restricted client class (notably AAPs). |
| GO:0051082 unfolded protein binding | IBA GO_REF:0000033 | MODIFY | Summary: IBA annotation for unfolded protein binding. GO:0051082 is now formally obsolete. CSH3 is not a general unfolded protein binder; it is a specialized ER membrane chaperone for amino acid permeases. Reason: GO:0051082 is now formally obsolete. 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 replacements: protein folding chaperone Supporting Evidence: file:CANAL/CSH3/CSH3-deep-research-falcon.md Csh3p is not a transporter and not an enzyme; instead, it is best understood as a fungal ER membrane "packaging/folding chaperone" whose primary role is to enable the proper biogenesis and ER exit of amino-acid permeases. |
| GO:0005783 endoplasmic reticulum | IDA PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | ACCEPT | Summary: IDA annotation for ER localization from the key characterization paper. 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. Supporting Evidence: PMID:14756779 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. |
| GO:0005886 plasma membrane | IDA PMID:19824013 Analysis of Candida albicans plasma membrane proteome. | REMOVE | Summary: IDA annotation for plasma membrane localization from a C. albicans plasma membrane proteome study. The available evidence does not support plasma membrane localization as the site of CSH3 function. Reason: PMID:19824013 is a broad subproteomic survey that identified many membrane proteins, including proteins with unknown membrane localization. In contrast, the CSH3-focused literature identifies CSH3 as a Shr3-family ER membrane packaging/folding chaperone, and a functional Csh3p-GFP fusion localizes to the perinuclear rim and ER-like cytoplasmic network. The strongest interpretation is that CSH3 acts in the ER to enable plasma membrane localization of amino acid permease clients; CSH3 itself should not be annotated as a plasma membrane protein. Supporting Evidence: PMID:19824013 a total of 214 membrane proteins were identified, including 41 already described as plasma membrane proteins, 20 plasma membrane associated proteins, and 22 proteins with unknown membrane localisation. file:CANAL/CSH3/CSH3-deep-research-falcon.md A functional Csh3p-GFP fusion shows perinuclear rim and ER-like cytoplasmic network fluorescence, consistent with endoplasmic reticulum localization. |
| GO:0030447 filamentous growth | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for filamentous growth. csh3-delta mutants are unable to switch morphologies on solid and liquid media. 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. Supporting Evidence: PMID:14756779 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 |
| GO:0031669 cellular response to nutrient levels | IMP PMID:16227594 Divergence of Stp1 and Stp2 transcription factors in Candida... | KEEP AS NON CORE | Summary: IMP annotation for cellular response to nutrient levels from the amino acid sensing/SPS pathway literature. Reason: CSH3 is functionally upstream of amino-acid sensing and nutrient response because it enables ER folding/exit of amino acid permeases and likely affects localization of the Ssy1-like amino acid sensor. This supports a nutrient-response phenotype, but the direct function remains ER membrane packaging/folding of permease clients rather than a nutrient-response signaling activity. Supporting Evidence: PMID:16227594 Candida albicans possesses a plasma membrane-localized sensor of extracellular amino acids. PMID:16227594 The shorter active form of Stp2 activates genes required for amino acid uptake. file:CANAL/CSH3/CSH3-deep-research-falcon.md Csh3p functions upstream of amino acid uptake and intersects the SPS amino-acid sensing pathway because proper localization of AAPs, and likely Ssy1, is required for extracellular amino-acid responses. |
| GO:0034605 cellular response to heat | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for heat response from the CSH3 characterization paper. 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. |
| GO:0036168 filamentous growth of a population of unicellular organisms in response to heat | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for heat-induced filamentous growth from the CSH3 characterization paper. 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. |
| GO:0036178 filamentous growth of a population of unicellular organisms in response to neutral pH | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for pH-induced filamentous growth. 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. |
| GO:0036180 filamentous growth of a population of unicellular organisms in response to biotic stimulus | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for biotic stimulus-induced filamentous growth. Reason: Same rationale as other filamentous growth annotations -- downstream phenotypic consequence of impaired amino acid permease biogenesis. Not a core function. |
| GO:0036187 cell growth mode switching, budding to filamentous | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for budding-to-filamentous growth switching. Reason: Morphological switching defect is a downstream consequence of CSH3's role in amino acid permease biogenesis. Not a core function. Supporting Evidence: PMID:14756779 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. |
| GO:0036244 cellular response to neutral pH | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for response to neutral pH. Reason: Downstream phenotypic effect of impaired amino acid permease biogenesis. Not a core function. |
| GO:0043090 amino acid import | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | ACCEPT | Summary: IMP annotation for amino acid import. The csh3-delta mutant has reduced amino acid uptake capacity. 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. Supporting Evidence: PMID:14756779 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 file:CANAL/CSH3/CSH3-deep-research-falcon.md Direct C. albicans genetic and physiological analysis indicates CSH3 is required for high-capacity amino acid uptake, consistent with impaired functional expression and/or plasma membrane localization of multiple AAPs in its absence. |
| GO:0051082 unfolded protein binding | ISS PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | MODIFY | Summary: ISS annotation for unfolded protein binding by sequence similarity to S. cerevisiae Shr3p. GO:0051082 is now formally obsolete. Reason: Same rationale as the IBA annotation. GO:0051082 is now formally obsolete. 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 replacements: protein folding chaperone |
| GO:0051082 unfolded protein binding | IGI PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | MODIFY | Summary: IGI annotation for unfolded protein binding based on genetic interaction with S. cerevisiae SHR3. GO:0051082 is now formally obsolete. Reason: Same rationale as the IBA and ISS annotations. GO:0051082 is now formally obsolete. 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 replacements: protein folding chaperone |
| GO:1900436 positive regulation of filamentous growth of a population of unicellular organisms in response to starvation | IMP PMID:14756779 An ER packaging chaperone determines the amino acid uptake c... | KEEP AS NON CORE | Summary: IMP annotation for positive regulation of starvation-induced filamentous growth. Reason: Downstream phenotypic consequence of impaired amino acid sensing/uptake due to loss of CSH3 function. Not a core molecular function. |
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