CSH3

Existing Annotations Review

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 proposed for obsoletion. CSH3 is not a general unfolded protein binder; it is a specialized ER membrane chaperone for amino acid permeases. 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 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 proposed for obsoletion. 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 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 proposed for obsoletion. 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 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.

Core Functions

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:

protein folding chaperone

Directly Involved In:

endoplasmic reticulum to Golgi vesicle-mediated transport amino acid import

Cellular Locations:

endoplasmic reticulum membrane

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

PMID:14756779

An ER packaging chaperone determines the amino acid uptake capacity and virulence of Candida albicans.

CSH3 is a functional and structural homolog of S. cerevisiae Shr3p.

"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."
csh3-delta mutant has reduced amino acid uptake and impaired morphological switching.

"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."
CSH3 haploinsufficiency affects virulence in mouse model.

"both CSH3/csh3delta heterozygous and csh3delta/csh3delta homozygous strains are unable to efficiently mount virulent infections in a mouse model."

PMID:16227594

Divergence of Stp1 and Stp2 transcription factors in Candida albicans places virulence factors required for proper nutrient acquisition under amino acid control.

PMID:19824013

Analysis of Candida albicans plasma membrane proteome.

file:CANAL/CSH3/CSH3-deep-research-falcon.md

Deep research report on CSH3 (Falcon/Edison Scientific Literature)

CSH3 is a Candida albicans Shr3-family ER membrane packaging/folding chaperone that enables amino acid permease biogenesis and ER exit; the evidence supports ER membrane localization, not a cell-surface or adhesin role.

Deep Research

Falcon

(CSH3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 20 citations 2 artifacts 2026-05-23T00:34:43.616866

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000017 I have extracted the following figures to answer your request: - **Quantitative Amino Acid Uptake Rates:** - **Figure 2A** (image-0 (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Candida albicans CSH3 (Csh3p; UniProt A0A1D8PLU5)

Scope and identity verification (mandatory)

The target protein is Csh3p, encoded by CSH3 in Candida albicans strain SC5314 (yeast). The gene/protein was experimentally characterized as a functional and structural homolog of Saccharomyces cerevisiae Shr3p, an ER-resident membrane factor required for efficient functional expression of amino-acid permeases (AAPs). The C. albicans protein shares reported sequence similarity with Shr3p and is predicted to be an integral membrane protein with four transmembrane segments, consistent with the Shr3/Psh3 (PF08229; IPR013248) family assignment provided in the UniProt context. (martinez2004anerpackaging pages 2-3, martinez2004anerpackaging pages 1-2)

1) Key concepts and current definitions

1.1 What Csh3p is (and is not)

Csh3p is not a transporter and not an enzyme; instead, it is best understood as a fungal ER membrane “packaging/folding chaperone” (also called a membrane-localized chaperone/escort) whose primary role is to enable the proper biogenesis and ER exit of a specific class of multipass plasma-membrane proteins—most prominently amino-acid permeases (AAPs). In the absence of Shr3-family proteins, client permeases are inserted into the ER membrane but fail to achieve productive folding/assembly, are excluded from ER export vesicles, and can be diverted to ER quality-control and degradation pathways. (martinez2004anerpackaging pages 1-2, silao2021aminoacidsensing pages 6-7, kota2007membranechaperoneshr3 pages 1-2, kota2007membranechaperoneshr3 pages 2-3)

1.2 Shr3-family ER chaperones: mechanistic model

Work in S. cerevisiae established the mechanistic paradigm for this family. Shr3 is an ER membrane-localized factor required specifically for ER-to-plasma-membrane localization of multiple AAPs, while many other secretory and membrane proteins traffic normally, indicating substrate-class specificity. (ljungdahl1992shr3anovel pages 2-3, ljungdahl1992shr3anovel pages 9-11)

Mechanistically, Shr3-family proteins:
- Assist early folding/assembly of nascent multipass transporters during co-translational membrane insertion.
- Help prevent nonproductive transmembrane-segment interactions and aggregation in the ER.
- Couple productive folding to COPII-mediated packaging and ER exit.
- Intersect with ER quality control; when Shr3 is absent, aggregated permeases can be targeted by ER-associated degradation (ERAD) pathways. (kota2007membranechaperoneshr3 pages 7-8, kota2007membranechaperoneshr3 pages 1-2, kota2007membranechaperoneshr3 pages 2-3, kota2007membranechaperoneshr3 pages 11-11)

Because C. albicans Csh3p is a functional homolog that complements S. cerevisiae shr3Δ phenotypes, these mechanistic principles are widely used as structure/function inference for Csh3p in C. albicans. (martinez2004anerpackaging pages 2-3, martinez2004anerpackaging pages 8-9)

2) Molecular function, pathway context, and cellular localization of C. albicans Csh3p

2.1 Subcellular localization

A functional Csh3p–GFP fusion shows perinuclear rim and ER-like cytoplasmic network fluorescence, consistent with endoplasmic reticulum localization. (martinez2004anerpackaging pages 3-5, martinez2004anerpackaging media b7665d6c)

2.2 Primary molecular function: enabling functional expression of amino-acid permeases

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. A csh3Δ/csh3Δ mutant showed a decreased capacity to transport each amino acid tested, with some uptake phenotypes being extreme (e.g., lysine and phenylalanine uptake undetectable in the described assays). (martinez2004anerpackaging pages 3-5, martinez2004anerpackaging media b7665d6c)

Csh3p also shows gene-dosage sensitivity: CSH3/csh3Δ heterozygotes can exhibit uptake defects even when some signaling responses appear intact, supporting a model where Csh3p is rate-limiting for maximal permease output. (martinez2004anerpackaging pages 9-11, martinez2004anerpackaging pages 3-5)

2.3 Relationship to amino-acid sensing and the SPS pathway

C. albicans contains homologs of the SPS amino-acid sensing system (Ssy1–Ptr3–Ssy5), which activates transcriptional programs for amino-acid uptake via proteolytic processing of transcription factors (Stp1/Stp2) and induction of AAP genes. In a 2023 nutrient-acquisition review, this system is summarized and notes that AAPs are co-translated into the ER and are shuttled onward via the ER chaperone Shr3 (not necessarily distinguishing Shr3 vs. Csh3 by name in the excerpt), consistent with the conserved trafficking paradigm. (garbe2023nutrientacquisitionand pages 21-25)

In C. albicans, Martínez & Ljungdahl explicitly predict that loss of Csh3p will retain AAPs in the ER (lowering permease abundance at the plasma membrane) and, because of the SPS pathway’s reliance on a plasma-membrane sensor (Ssy1-like), that the Ssy1 homolog may also be retained in the ER, thereby attenuating downstream SPS signaling and AAP gene expression. (martinez2004anerpackaging pages 8-9)

3) Phenotypes and quantitative evidence

3.1 Amino-acid uptake phenotypes (quantitative)

In uptake assays using radiolabeled substrates, the csh3Δ/csh3Δ mutant exhibited:
- Undetectable lysine and phenylalanine uptake
- Greatly diminished histidine and proline uptake
- Increased adenine uptake (a specificity control suggesting the defect is not a global uptake collapse) (martinez2004anerpackaging pages 3-5, martinez2004anerpackaging media b7665d6c)

Methods/statistics context reported in the primary study include initial uptake-rate measurements using 14C-labeled amino acids, and uptake activity expressed in nmol·min⁻¹ units; experimental details include buffering conditions and glucose supplementation. (martinez2004anerpackaging pages 12-13)

3.2 Morphogenesis / filamentation

A central biological implication is that amino-acid-induced morphogenic switching (filamentation) depends on CSH3. csh3Δ/csh3Δ mutants show severely reduced ability to switch morphologies in response to amino-acid stimuli, while responses to non–amino-acid cues are comparatively preserved, supporting functional specificity tied to amino-acid uptake/sensing circuits. (martinez2004anerpackaging pages 9-11, martinez2004anerpackaging pages 8-9)

3.3 Virulence (mouse systemic infection) with specific outcome measures

In a mouse intravenous infection model, CSH3 is required for efficient virulence:
- Wild-type CSH3/CSH3 C. albicans killed hosts rapidly (reported as all mice dead within 9 days in one comparison; an alternate wild-type comparator killed all by day 5).
- Both CSH3/csh3Δ heterozygous and csh3Δ/csh3Δ homozygous strains were markedly attenuated, with ~50% of mice alive at day 16 and some animals surviving to the end of a 30-day observation period. (martinez2004anerpackaging pages 8-9)

These findings directly connect an ER chaperone for nutrient transporters to pathogenic fitness, and they support the authors’ inference that C. albicans uses amino acids (likely as nitrogen sources) during mammalian infection and that high-capacity amino-acid uptake is a virulence-enabling trait. (martinez2004anerpackaging pages 8-9, martinez2004anerpackaging pages 1-2)

4) Recent developments and latest research (emphasis on 2023–2024)

4.1 2023 synthesis in C. albicans nutrient-acquisition literature

A 2023 review on nutrient acquisition and metabolic adaptation in C. albicans summarizes the SPS signaling cascade and places ER chaperone–mediated trafficking of AAPs (via Shr3-family function) as an enabling layer for amino-acid uptake programs. While the excerpted sections do not discuss CSH3 specifically by name or provide new quantitative Csh3-specific data, the inclusion of Shr3-mediated trafficking in a contemporary virulence-metabolism synthesis indicates ongoing relevance of this mechanism as a core concept in the field. (garbe2023nutrientacquisitionand pages 21-25)

4.2 Mechanistic maturation of the Shr3 paradigm

Although not C. albicans-specific, mechanistic work in the Shr3 family continues to refine concepts of co-translational assistance, transient chaperone–substrate interactions, and integration with quality-control routes (ERAD). A 2019 review consolidates these ideas and explicitly lists orthologs including Csh3 in C. albicans, situating it among ER factors that link folding/assembly to ER export. (diallinas2019transportermembranetraffic pages 2-4)

Limitation of the present evidence set: a 2023 Journal of Cell Biology primary paper on Shr3 is known to exist (metadata observed during search), but its full text was not successfully retrieved in the current tool context; therefore, I do not quote or rely on its specific claims here. (unretrieved in this run)

5) Applications and real-world implementations

5.1 Csh3p as a node connecting nutrient uptake to virulence

Because Csh3p is required for functional expression of multiple AAPs, it acts as a bottleneck control point for amino-acid uptake capacity. In the context of infection biology, the mouse systemic infection attenuation observed for both heterozygous and homozygous mutants suggests that partial reductions in this node can have large effects on host-pathogen outcomes. (martinez2004anerpackaging pages 8-9, martinez2004anerpackaging pages 9-11)

5.2 Conceptual/therapeutic relevance

The primary literature emphasizes that Csh3p/Shr3 homologs are fungal-specific and required for efficient permease biogenesis and virulence-associated growth. This makes Shr3-family chaperones conceptually attractive as antifungal target classes (pathogen-selective membrane biogenesis factors), although the evidence assembled here does not include direct drug-development studies targeting Csh3p. (martinez2004anerpackaging pages 9-11, diallinas2019transportermembranetraffic pages 2-4)

6) Expert opinions and authoritative interpretations

Across primary and review literature, the expert consensus is that 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)
- Function at the interface of folding/assembly, quality control (ERAD), and COPII packaging
- Are conserved across fungi with orthologs including Csh3 (Candida) and Psh3 (Schizosaccharomyces), reinforcing functional inference for less extensively characterized family members. (diallinas2019transportermembranetraffic pages 2-4, ljungdahl1992shr3anovel pages 2-3, ljungdahl1992shr3anovel pages 9-11)

Evidence summary table

Aspect	Key evidence/notes	Key sources
identity/domains	Candida albicans CSH3 encodes Csh3p, a functional and structural homolog of Saccharomyces cerevisiae Shr3p. The reported protein has four transmembrane segments, ~36% identity / 48% similarity to S. cerevisiae Shr3p, matching the UniProt-assigned Shr3/Psh3 family context rather than an unrelated CSH3 symbol from another organism. (martinez2004anerpackaging pages 2-3, martinez2004anerpackaging pages 1-2)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x; Ljungdahl et al. 1992, DOI: https://doi.org/10.1016/0092-8674(92)90515-e
localization	Functional Csh3p-GFP localizes to the perinuclear rim and a filamentous cytoplasmic network, consistent with the endoplasmic reticulum (ER). Reviews and comparative studies consistently describe Csh3/Shr3 proteins as ER-membrane-localized chaperones. (martinez2004anerpackaging pages 3-5, silao2021aminoacidsensing pages 6-7, martinez2004anerpackaging media b7665d6c)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x; Silao & Ljungdahl 2021, DOI: https://doi.org/10.3390/pathogens11010005
molecular function	Csh3p is not an enzyme or transporter; it is a specialized ER packaging/folding chaperone required for the productive biogenesis of amino acid permeases (AAPs). By analogy with Shr3-family mechanistic work, it assists early folding/assembly of multipass transporters, promotes their COPII-dependent ER exit, and helps prevent aggregation and premature ERAD. (martinez2004anerpackaging pages 1-2, kota2007membranechaperoneshr3 pages 7-8, kota2007membranechaperoneshr3 pages 1-2, diallinas2019transportermembranetraffic pages 2-4)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x; Kota et al. 2007, DOI: https://doi.org/10.1083/jcb.200612100; Diallinas & Martzoukou 2019, DOI: https://doi.org/10.1111/febs.15078
client proteins	The best-supported clients are the AAP family in C. albicans; the genome was noted to encode ~22 AAP-related ORFs. The literature also predicts dependence of the Ssy1 amino-acid sensor/permease-like component on Csh3 for proper plasma-membrane localization, consistent with Shr3-family substrate specificity for related multipass membrane proteins. (martinez2004anerpackaging pages 1-2, martinez2004anerpackaging pages 8-9, garbe2023nutrientacquisitionand pages 21-25)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x; Garbe 2023 (review context summarized in available text)
pathway context	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. In the broader model, extracellular amino acids activate Ssy1-Ptr3-Ssy5, causing Stp1/Stp2 processing and induction of AAP genes; Csh3 is needed so these induced permeases become functional at the plasma membrane. (martinez2004anerpackaging pages 8-9, garbe2023nutrientacquisitionand pages 21-25, silao2021aminoacidsensing pages 6-7)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x; Silao & Ljungdahl 2021, DOI: https://doi.org/10.3390/pathogens11010005
phenotypes	csh3Δ/csh3Δ mutants show broad defects in amino-acid utilization and uptake, including inability to efficiently use several amino acids as nitrogen sources and failure to undergo amino-acid-induced filamentation. CSH3/csh3Δ heterozygotes are haploinsufficient for high-capacity uptake, showing intermediate uptake defects while often retaining amino-acid-induced morphogenetic signaling. (martinez2004anerpackaging pages 9-11, martinez2004anerpackaging pages 3-5, martinez2004anerpackaging pages 1-2)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x
virulence data	In a mouse intravenous infection model using 1 × 10^6 cells per inoculum, wild-type CSH3/CSH3 strains killed all mice rapidly, whereas both heterozygous and homozygous csh3 mutants were markedly attenuated. Reported summary outcomes include wild type killing all mice within 9 days (one wild-type comparator by day 5), while mutant groups showed prolonged survival, with 50% alive at day 16 and some animals surviving to day 30. (martinez2004anerpackaging pages 8-9)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x
quantitative measures	Uptake assays measured initial rates with 14C-labeled amino acids at 50 mM substrate and reported activity in nmol min^-1. Quantitatively, the null mutant had undetectable lysine and phenylalanine uptake, greatly diminished histidine and proline uptake, and even increased adenine uptake; figure-based evidence also shows gene-dosage effects in heterozygotes and a 5 h proline-uptake induction time course. (martinez2004anerpackaging pages 3-5, martinez2004anerpackaging pages 12-13, martinez2004anerpackaging media b7665d6c)	Martínez & Ljungdahl 2004, DOI: https://doi.org/10.1046/j.1365-2958.2003.03845.x

Table: This table summarizes the experimentally supported functional annotation of Candida albicans Csh3p (CSH3; UniProt A0A1D8PLU5), including identity, localization, mechanism, pathway placement, and phenotype/virulence evidence. It is useful as a concise evidence map for interpreting this Shr3-family ER membrane chaperone.

Key visual evidence retrieved in this run

Csh3p–GFP ER localization micrographs (Fig. 2C) (martinez2004anerpackaging media b7665d6c)
Quantitative amino-acid uptake rates across genotypes (Fig. 2A) (martinez2004anerpackaging media b7665d6c)
Proline uptake induction time course (Fig. 6B) (martinez2004anerpackaging media b7665d6c)
Mouse survival curves demonstrating virulence attenuation (Fig. 7A) (martinez2004anerpackaging media b7665d6c)

References (URLs and publication dates where available)

Ljungdahl PO, Gimeno CJ, Styles CA, Fink GR. SHR3: A novel component of the secretory pathway specifically required for localization of amino acid permeases in yeast. Cell. 1992-10. https://doi.org/10.1016/0092-8674(92)90515-e (ljungdahl1992shr3anovel pages 2-3, ljungdahl1992shr3anovel pages 9-11)
Martínez P, Ljungdahl PO. An ER packaging chaperone determines the amino acid uptake capacity and virulence of Candida albicans. Molecular Microbiology. 2004-01. https://doi.org/10.1046/j.1365-2958.2003.03845.x (martinez2004anerpackaging pages 8-9, martinez2004anerpackaging pages 3-5, martinez2004anerpackaging pages 2-3, martinez2004anerpackaging media b7665d6c)
Kota J, Gilstring CF, Ljungdahl PO. Membrane chaperone Shr3 assists in folding amino acid permeases preventing precocious ERAD. J Cell Biol. 2007-02. https://doi.org/10.1083/jcb.200612100 (kota2007membranechaperoneshr3 pages 7-8, kota2007membranechaperoneshr3 pages 2-3)
Diallinas G, Martzoukou O. Transporter membrane traffic and function: lessons from a mould. FEBS J. 2019-12. https://doi.org/10.1111/febs.15078 (diallinas2019transportermembranetraffic pages 2-4)
Silao FGS, Ljungdahl PO. Amino Acid Sensing and Assimilation by the Fungal Pathogen Candida albicans in the Human Host. Pathogens. 2021-12. https://doi.org/10.3390/pathogens11010005 (silao2021aminoacidsensing pages 6-7)
Garbe E. Nutrient acquisition and metabolic adaptation in the context of Candida albicans virulence. 2023. (bibliographic details incomplete in retrieved record) (garbe2023nutrientacquisitionand pages 21-25)

References

(martinez2004anerpackaging pages 2-3): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(martinez2004anerpackaging pages 1-2): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(silao2021aminoacidsensing pages 6-7): Fitz Gerald S. Silao and Per O. Ljungdahl. Amino acid sensing and assimilation by the fungal pathogen candida albicans in the human host. Pathogens, 11:5, Dec 2021. URL: https://doi.org/10.3390/pathogens11010005, doi:10.3390/pathogens11010005. This article has 44 citations.
(kota2007membranechaperoneshr3 pages 1-2): Jhansi Kota, C. Fredrik Gilstring, and Per O. Ljungdahl. Membrane chaperone shr3 assists in folding amino acid permeases preventing precocious erad. The Journal of Cell Biology, 176:617-628, Feb 2007. URL: https://doi.org/10.1083/jcb.200612100, doi:10.1083/jcb.200612100. This article has 128 citations.
(kota2007membranechaperoneshr3 pages 2-3): Jhansi Kota, C. Fredrik Gilstring, and Per O. Ljungdahl. Membrane chaperone shr3 assists in folding amino acid permeases preventing precocious erad. The Journal of Cell Biology, 176:617-628, Feb 2007. URL: https://doi.org/10.1083/jcb.200612100, doi:10.1083/jcb.200612100. This article has 128 citations.
(ljungdahl1992shr3anovel pages 2-3): Per O. Ljungdahl, Carlos J. Gimeno, Cora A. Styles, and Gerald R. Fink. Shr3: a novel component of the secretory pathway specifically required for localization of amino acid permeases in yeast. Cell, 71:463-478, Oct 1992. URL: https://doi.org/10.1016/0092-8674(92)90515-e, doi:10.1016/0092-8674(92)90515-e. This article has 241 citations and is from a highest quality peer-reviewed journal.
(ljungdahl1992shr3anovel pages 9-11): Per O. Ljungdahl, Carlos J. Gimeno, Cora A. Styles, and Gerald R. Fink. Shr3: a novel component of the secretory pathway specifically required for localization of amino acid permeases in yeast. Cell, 71:463-478, Oct 1992. URL: https://doi.org/10.1016/0092-8674(92)90515-e, doi:10.1016/0092-8674(92)90515-e. This article has 241 citations and is from a highest quality peer-reviewed journal.
(kota2007membranechaperoneshr3 pages 7-8): Jhansi Kota, C. Fredrik Gilstring, and Per O. Ljungdahl. Membrane chaperone shr3 assists in folding amino acid permeases preventing precocious erad. The Journal of Cell Biology, 176:617-628, Feb 2007. URL: https://doi.org/10.1083/jcb.200612100, doi:10.1083/jcb.200612100. This article has 128 citations.
(kota2007membranechaperoneshr3 pages 11-11): Jhansi Kota, C. Fredrik Gilstring, and Per O. Ljungdahl. Membrane chaperone shr3 assists in folding amino acid permeases preventing precocious erad. The Journal of Cell Biology, 176:617-628, Feb 2007. URL: https://doi.org/10.1083/jcb.200612100, doi:10.1083/jcb.200612100. This article has 128 citations.
(martinez2004anerpackaging pages 8-9): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(martinez2004anerpackaging pages 3-5): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(martinez2004anerpackaging media b7665d6c): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(martinez2004anerpackaging pages 9-11): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(garbe2023nutrientacquisitionand pages 21-25): E Garbe. Nutrient acquisition and metabolic adaptation in the context of candida albicans virulence. Unknown journal, 2023.
(martinez2004anerpackaging pages 12-13): Paula Martínez and Per O. Ljungdahl. An er packaging chaperone determines the amino acid uptake capacity and virulence of candida albicans. Molecular Microbiology, 51:371-384, Jan 2004. URL: https://doi.org/10.1046/j.1365-2958.2003.03845.x, doi:10.1046/j.1365-2958.2003.03845.x. This article has 74 citations and is from a domain leading peer-reviewed journal.
(diallinas2019transportermembranetraffic pages 2-4): George Diallinas and Olga Martzoukou. Transporter membrane traffic and function: lessons from a mould. The FEBS Journal, 286:4861-4875, Dec 2019. URL: https://doi.org/10.1111/febs.15078, doi:10.1111/febs.15078. This article has 32 citations.

Artifacts

Edison artifact artifact-00

Citations

garbe2023nutrientacquisitionand pages 21-25
martinez2004anerpackaging pages 8-9
martinez2004anerpackaging pages 12-13
diallinas2019transportermembranetraffic pages 2-4
silao2021aminoacidsensing pages 6-7
martinez2004anerpackaging pages 2-3
martinez2004anerpackaging pages 1-2
martinez2004anerpackaging pages 3-5
martinez2004anerpackaging pages 9-11
https://doi.org/10.1046/j.1365-2958.2003.03845.x;
https://doi.org/10.1016/0092-8674(92
https://doi.org/10.3390/pathogens11010005
https://doi.org/10.1083/jcb.200612100;
https://doi.org/10.1111/febs.15078
https://doi.org/10.1046/j.1365-2958.2003.03845.x
https://doi.org/10.1083/jcb.200612100
https://doi.org/10.1046/j.1365-2958.2003.03845.x,
https://doi.org/10.3390/pathogens11010005,
https://doi.org/10.1083/jcb.200612100,
https://doi.org/10.1111/febs.15078,

📄 View Raw YAML

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).
    additional_reference_ids:
    - file:CANAL/CSH3/CSH3-deep-research-falcon.md
    supported_by:
    - reference_id: file:CANAL/CSH3/CSH3-deep-research-falcon.md
      supporting_text: >-
        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).
- 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
    additional_reference_ids:
    - file:CANAL/CSH3/CSH3-deep-research-falcon.md
    supported_by:
    - reference_id: file:CANAL/CSH3/CSH3-deep-research-falcon.md
      supporting_text: >-
        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.
- 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 a C. albicans plasma
      membrane proteome study. The available evidence does not support plasma
      membrane localization as the site of CSH3 function.
    action: REMOVE
    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.
    additional_reference_ids:
    - PMID:14756779
    - file:CANAL/CSH3/CSH3-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:19824013
      supporting_text: >-
        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.
    - reference_id: file:CANAL/CSH3/CSH3-deep-research-falcon.md
      supporting_text: >-
        A functional Csh3p-GFP fusion shows perinuclear rim and ER-like cytoplasmic
        network fluorescence, consistent with endoplasmic reticulum localization.
- 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 the amino
      acid sensing/SPS pathway literature.
    action: KEEP_AS_NON_CORE
    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.
    additional_reference_ids:
    - file:CANAL/CSH3/CSH3-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:16227594
      supporting_text: >-
        Candida albicans possesses a plasma membrane-localized sensor of extracellular
        amino acids.
    - reference_id: PMID:16227594
      supporting_text: >-
        The shorter active form of Stp2 activates genes required for amino acid uptake.
    - reference_id: file:CANAL/CSH3/CSH3-deep-research-falcon.md
      supporting_text: >-
        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.
- 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.
    additional_reference_ids:
    - file:CANAL/CSH3/CSH3-deep-research-falcon.md
    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
    - reference_id: file:CANAL/CSH3/CSH3-deep-research-falcon.md
      supporting_text: >-
        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.
- 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: []
- id: file:CANAL/CSH3/CSH3-deep-research-falcon.md
  title: Deep research report on CSH3 (Falcon/Edison Scientific Literature)
  findings:
  - statement: CSH3 is a Candida albicans Shr3-family ER membrane packaging/folding chaperone that enables amino acid permease biogenesis and ER exit; the evidence supports ER membrane localization, not a cell-surface or adhesin role.
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

Gene Description

Existing Annotations Review

Core Functions

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.

References

Deep Research

Falcon

Comprehensive Research Report: Candida albicans CSH3 (Csh3p; UniProt A0A1D8PLU5)

Scope and identity verification (mandatory)

1) Key concepts and current definitions

1.1 What Csh3p is (and is not)

1.2 Shr3-family ER chaperones: mechanistic model

2) Molecular function, pathway context, and cellular localization of C. albicans Csh3p

2.1 Subcellular localization

2.2 Primary molecular function: enabling functional expression of amino-acid permeases

2.3 Relationship to amino-acid sensing and the SPS pathway

3) Phenotypes and quantitative evidence

3.1 Amino-acid uptake phenotypes (quantitative)

3.2 Morphogenesis / filamentation

3.3 Virulence (mouse systemic infection) with specific outcome measures

4) Recent developments and latest research (emphasis on 2023–2024)

4.1 2023 synthesis in C. albicans nutrient-acquisition literature

4.2 Mechanistic maturation of the Shr3 paradigm

5) Applications and real-world implementations

5.1 Csh3p as a node connecting nutrient uptake to virulence

5.2 Conceptual/therapeutic relevance

6) Expert opinions and authoritative interpretations

Evidence summary table

Key visual evidence retrieved in this run

References (URLs and publication dates where available)

Artifacts

Citations

📄 View Raw YAML