hgh1 is the Schizosaccharomyces pombe member of the conserved HGH1 protein family (orthologous to Saccharomyces cerevisiae Hgh1 and human HGH1/FAM203). It is a small (~356 aa, ~41 kDa) soluble, non-catalytic protein built on an armadillo/HEAT-like all-alpha repeat scaffold with the family-diagnostic HGH1 N- and C-terminal domains (Pfam DUF383/DUF384). In budding yeast the ortholog is a dedicated co-chaperone for the biogenesis of eukaryotic elongation factor 2 (eEF2): it binds the structurally dynamic central domain III of nascent eEF2 and recruits the chaperonin TRiC/CCT (and potentially Hsp90 via a Cns1 co-chaperone), shielding domain III and promoting productive folding of the essential eEF2 GTPase, before dissociating once folding is complete. On this basis hgh1 is annotated as a cytoplasmic protein-folding chaperone acting in co-translational protein folding. The eEF2-chaperone function has not been directly demonstrated in fission yeast; the fission-yeast gene is dispensable for viability, and its S. pombe-specific molecular activity, client range, and biological role remain to be experimentally established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization inferred by UniProt SubCell mapping. Consistent with a soluble co-chaperone lacking signal/transmembrane features and with the cytosolic site of eEF2/TRiC-assisted folding. Reason: hgh1 has no signal peptide or transmembrane segment (UniProt Q10498) and belongs to a soluble ARM-repeat family; the cytoplasm is where the eEF2/TRiC co-translational folding it participates in occurs. Location is well supported but not itself a core function. Supporting Evidence: PMID:30876804 the highly conserved protein Hgh1 (FAM203 in humans) is a chaperone that cooperates with TRiC in eEF2 folding. |
| GO:0044183 protein folding chaperone | ISO GO_REF:0000024 | ACCEPT | Summary: Molecular function transferred by orthology from S. cerevisiae Hgh1, which acts as a (non-ATP-dependent) co-chaperone/adaptor that binds nascent eEF2 and recruits the chaperonin TRiC. "protein folding chaperone" (GO:0044183, not the ATP-dependent child GO:0140662) is the appropriate molecular function for this adaptor-type role. Reason: The ortholog's chaperone activity toward eEF2 is experimentally established (PMID:30876804) and the orthology (single-copy KOG2973; reciprocal PomBase ortholog calls to S. cerevisiae YGR187C and human HGH1/FAM203) is unambiguous. Hgh1 is not an ATP-driven foldase; the general MF term is correct. This is the core molecular function, though it is inferred rather than measured in S. pombe. Supporting Evidence: PMID:30876804 Hgh1 is an armadillo repeat protein that binds to the dynamic central domain III of eEF2 via a bipartite interface. |
| GO:0051083 'de novo' cotranslational protein folding | ISO GO_REF:0000024 | ACCEPT | Summary: Biological process transferred by orthology. The ortholog assists folding of nascent, ribosome-associated eEF2 co-translationally, recruiting TRiC and shielding domain III until the GTPase module folds. This is consistent with the co-translational, de-novo-folding scope of GO:0051083. Reason: Matches the experimentally described mechanism of the ortholog (assists folding of newly synthesized eEF2, cooperating with the chaperonin). Retained as the core biological process, inferred by orthology. Supporting Evidence: PMID:30876804 In the absence of Hgh1, a substantial fraction of newly synthesized eEF2 is degraded or aggregates. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Cytoplasmic localization transferred by sequence similarity from UniProt P48362 (S. cerevisiae Hgh1). Redundant with the IEA SubCell annotation but concordant and well motivated by the family's soluble, cytosolic character. Reason: Same well-supported cytoplasmic location as the IEA row, from an orthology-based (ISS) source; concordant with the site of eEF2 folding. Location, non-core. Supporting Evidence: PMID:30876804 the highly conserved protein Hgh1 (FAM203 in humans) is a chaperone that cooperates with TRiC in eEF2 folding. |
| GO:0005634 nucleus | ISO GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Nuclear "is_active_in" transferred by orthology. eEF2 biogenesis is a cytoplasmic, co-translational process, and both the fission-yeast protein and the characterized S. cerevisiae ortholog are described as cytosolic (UniProt Q10498/P48362 SUBCELLULAR LOCATION: Cytoplasm). No molecular role for HGH1 proteins in the nucleus has been demonstrated; a nuclear site of action is not supported by the established mechanism. Reason: The known function of the HGH1 family (recruiting TRiC/Hsp90 to fold nascent cytoplasmic eEF2) is incompatible with a nuclear site of action. The nuclear "is_active_in" appears to be an over-broad ISO transfer from a high-throughput localization dataset rather than a functionally meaningful nuclear activity. There is no evidence for a nuclear function in S. pombe; flagging as over-annotation rather than removing, since a minor nucleocytoplasmic pool cannot be excluded and the curator's source evidence has not been read. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: SGD:S000003419 · HGH1 (S. cerevisiae, YGR187C) SUPPORTS SOURCE BUT NOT TARGET The eEF2 co-chaperone activity of the S. cerevisiae ortholog is a cytoplasmic, co-translational process; an is_active_in nucleus qualifier does not reflect the site where this molecular function is executed and should not propagate as a functional (is_active_in) annotation to hgh1. |
| GO:0005737 cytoplasm | ISO GO_REF:0000024 | ACCEPT | Summary: Cytoplasmic site of action transferred by orthology. This is where the eEF2/TRiC co-translational folding cycle occurs, so "is_active_in cytoplasm" correctly captures the compartment in which hgh1's inferred molecular function is executed. Reason: Concordant with the established cytosolic mechanism of the ortholog and with the located_in cytoplasm annotations. Non-core location/site-of-action term. Supporting Evidence: PMID:30876804 Hgh1 binding recruits TRiC to the C-terminal eEF2 module and prevents unproductive interactions of domain III, allowing efficient folding of the N-terminal GTPase module. |
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Download this section (compressed HTML)Q: Does S. pombe hgh1 physically bind eEF2 and the CCT/TRiC chaperonin, and is it required for efficient eEF2 folding and steady-state abundance in fission yeast, as its S. cerevisiae ortholog is?
Suggested experts: Molecular chaperone / eEF2 biogenesis biochemists (e.g. authors of PMID:30876804), Fission-yeast proteostasis researchers
Q: What accounts for the pleiotropic stress-response phenotypes of hgh1 deletion, and are they downstream of altered eEF2 biogenesis/translation elongation?
Suggested experts: Fission-yeast functional-genomics / phenomics groups
Experiment: Affinity-purify tagged hgh1 from S. pombe and identify interactors by mass spectrometry; specifically test for eEF2 (ef2) and CCT/TRiC subunits and Hsp90. Complement with in vitro binding to recombinant eEF2 and eEF2 domain-III fragments.
Hypothesis: hgh1 is a conserved co-chaperone that binds nascent eEF2 domain III and recruits TRiC, required for efficient eEF2 folding in S. pombe.
Type: co-immunoprecipitation / affinity-MS and in vitro binding
Experiment: Construct an hgh1-delta strain; quantify soluble vs aggregated eEF2 and total eEF2 levels, measure translation-elongation rate/fidelity (e.g. ribosome profiling, readthrough reporters), and phenotype under the stresses flagged in high-throughput screens.
Hypothesis: Loss of hgh1 reduces mature eEF2 and impairs translation elongation under stress.
Type: genetics + proteomics + ribosome profiling
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether S. pombe hgh1 actually performs the eEF2 co-chaperone function is unmeasured: no fission-yeast experiment has shown hgh1 binds eEF2 (or its domain III), recruits TRiC/CCT or Hsp90, or is required for eEF2 folding, abundance, or stability. Every molecular-function and biological-process annotation for hgh1 is an electronic orthology transfer (ISO from S. cerevisiae; GO_REF:0000024), not a direct observation.
OPEN BIOLOGYCURATION MF_DARK
What is known: The mechanism is firmly established for the S. cerevisiae ortholog: Hgh1 is an armadillo-repeat chaperone that binds nascent eEF2 domain III and recruits TRiC to fold the eEF2 GTPase module (PMID:30876804). Orthology of hgh1 to S. cerevisiae YGR187C and human HGH1/FAM203 is unambiguous (single-copy KOG2973; reciprocal ortholog calls), and hgh1 carries the diagnostic HGH1 domains on an ARM-type fold. What is missing is any S. pombe-specific functional assay.
Significance: eEF2 is essential and highly abundant; a dedicated biogenesis factor for it is a node where translation capacity and proteostasis intersect. Confirming (or refuting) the conserved role in fission yeast would validate the orthology-based annotation and clarify whether the pathway is universally conserved across yeasts.
What would resolve it: Test physical interaction of hgh1 with eEF2 (ef2/tef products) and with the CCT/TRiC subunits in S. pombe (co-IP, crosslinking); quantify mature eEF2 levels and aggregation in an hgh1-delta strain; assess translation-elongation and eEF2-folding phenotypes.
Provenance (the field's own admissions):
Gap: The biological role and loss-of-function consequences of hgh1 in fission yeast are largely undefined. Deletion is viable with normal morphology, so any requirement is conditional/quantitative; the mechanistic basis for the pleiotropic stress phenotypes reported in high-throughput screens (e.g. hydroxyurea/lithium sensitivity, caffeine resistance) is unknown and not obviously connected to eEF2 folding.
OPEN BIOLOGY BP_DARK
What is known: PomBase records hgh1 deletion as viable (FYPO "viable vegetative cell population", "viable vegetative cell with normal cell morphology") with a broad set of condition-specific stress phenotypes from genome-wide screens; characterisation status is "biological role inferred". The client protein eEF2 is itself essential.
Significance: Understanding why an eEF2 biogenesis factor is dispensable, and what the stress phenotypes reflect, would reveal how much eEF2 folding depends on this dedicated co-chaperone versus general chaperone redundancy.
What would resolve it: Targeted phenotyping of an hgh1-delta strain under the flagged stresses with eEF2 readouts; epistasis with cct/TRiC and hsp90 co-chaperone mutants; measurement of translation elongation rate/fidelity.
Gap: Whether HGH1-family proteins act on clients other than eEF2, and whether hgh1 has any genuine nuclear function (as an "is_active_in nucleus" annotation suggests) rather than being exclusively a cytoplasmic eEF2 co-chaperone, is unknown.
OPEN BIOLOGY MF_DARK
What is known: All experimentally defined function of the family concerns cytoplasmic eEF2 folding; both hgh1 and its ortholog are annotated as cytoplasmic (UniProt SUBCELLULAR LOCATION). No non-eEF2 client and no nuclear molecular activity have been demonstrated.
Significance: Establishing the client range would determine whether HGH1 is a dedicated eEF2 factor or a more general folding adaptor, informing how conserved this proteostasis module is.
What would resolve it: Unbiased interactome (proximity labeling / affinity-MS) of hgh1 in S. pombe; test for any functional nuclear pool by localization and nuclear-anchoring/depletion assays.
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