Hyal2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004415 hyalurononglucosaminidase activity	IEA GO_REF:0000120	ACCEPT	Summary: The core molecular function. Naked mole rat HYAL2 has been cloned and shown to degrade hyaluronan in transfected cells, the catalytic proton donor and all family disulfides are retained, and UniProt assigns EC 3.2.1.35 on RuleBase evidence. Reason: This is the one annotation in the set with direct naked-mole-rat functional support. PMID:38052795 cloned HYAL2 of NMR into a piggyBac vector, expressed it in HeLa and HEK293T cells, and compared wild type against the G284A revertant of the mole-rat-specific A284G substitution. Both constructs degrade hyaluronan; the revertant leaves smaller product. That is a quantitative attenuation of a retained activity, not a loss of function, and per the review guidance it refines rather than abolishes the GO molecular function. The sequence agrees - UniProt annotates the proton donor at residue 135, which in the deposited sequence is the glutamate of the conserved GH56 DWEHW motif (positions 133-137 read D-W-E-H-W), and all five PIRSR disulfides are present. The apparent conflict in the human donor record (nine IDAs for this term plus one NOT\|enables IDA from PMID:11296287) reflects the weak, acid-requiring character of HYAL2 rather than a curation error - the enzyme works below pH 4 (PMID:9712871) yet has demonstrable physiological activity in vivo (PMID:18772348). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q12891 · human HYAL2 SUPPORTS TRANSFER Nine independent IDAs for this term in GOA. UniProtKB:O35632 · mouse Hyal2 SUPPORTS TRANSFER IMP from PMID:26887442 plus ISS. Supporting Evidence: PMID:38052795 A positively selected site G284 was also identified in NMR and DMR HYAL2 (Fig. 3c). We tested the effect of this mutation on NMR HYAL2. We did not observe difference when HA was incubated for two days, but the size and amount of HA was smaller after three days of incubation (Fig. 5i), suggesting that the substitution in G284 also contributes to the weaker HYAL2 in NMRs. PMID:38052795 as well as HYAL2 of NMR were cloned into a piggyBac vector file:HETGA/Hyal2/Hyal2-uniprot.txt EC=3.2.1.35 file:HETGA/Hyal2/Hyal2-uniprot.txt ACT_SITE 135 PMID:9712871 The HYAL2 protein was shown to have hyaluronidase activity below pH 4.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: The GPI anchor places mature HYAL2 in the plasma membrane; this is the primary site of its catalytic function and is asserted directly on the naked mole rat record. Reason: UniProt annotates cell membrane with a GPI lipid anchor for A0A0P6J1Y4 itself, and the topology follows from the cleaved signal peptide plus C-terminal GPI attachment. Human and mouse donors both carry multiple IDAs and an EXP. Since GO obsoleted the GPI-specific location terms (GO:0046658 and GO:0031225, both replaced_by GO:0005886), plasma membrane is now the correct and only available representation of the anchored state. Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SUBCELLULAR LOCATION: Cell membrane file:HETGA/Hyal2/Hyal2-uniprot.txt Lipid-anchor, GPI-anchor PMID:11296287 HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein.
GO:0005975 carbohydrate metabolic process	IEA GO_REF:0000120	MODIFY	Summary: Correct but far too general - an InterPro2GO and UniRule mapping at the level of all carbohydrate metabolism for a dedicated hyaluronan hydrolase. Reason: The annotation is not wrong, but it sits several levels above what is known. The source domain is InterPro:IPR018155, which is the hyaluronidase signature itself, so the mapping discards specificity the source already carries. The informative term is GO:0030214 hyaluronan catabolic process, which is what the enzyme actually does and which is separately supported here. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: hyaluronan catabolic process Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt -!- FUNCTION: Catalyzes hyaluronan degradation into small fragments that
GO:0046718 symbiont entry into host cell	IEA GO_REF:0000108	REMOVE	Summary: A mechanical inter-ontology consequence of the GO:0001618 virus receptor annotation, which is itself not defensible for this species. Reason: The WITH/FROM for this row is literally GO:0001618, so this annotation exists only because the virus receptor activity annotation exists. Removing that annotation removes this one with it. Independently, the process referred to is entry of jaagsiekte sheep retrovirus and enzootic nasal tumour virus, ovine and caprine betaretroviruses, into a host cell; there is no evidence that HYAL2 of Heterocephalus glaber participates in the entry of any virus, and the only rodent HYAL2 ever tested does not mediate entry of either virus. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE Sources checked: GO:0001618 · virus receptor activity SOURCE BAD The inference source is another annotation on this protein that is itself an unsupported ortholog projection. Supporting Evidence: PMID:16191204 Human Hyal2 binds the envelope (Env) proteins of these viruses and is functional as a receptor, but Hyal2 from mice does not bind Env nor does it mediate entry of either virus.
GO:0000302 response to reactive oxygen species	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from a single human IDA. Plausible in the naked mole rat, where hyaluronan is implicated in oxidative stress resistance, but that biology belongs to the polymer and CD44, not demonstrably to Hyal2. Reason: The human donor has one IDA (PMID:20554532). The naked mole rat context makes this superficially attractive - very-high-molecular-mass hyaluronan is cytoprotective against oxidative stress - but that protection is a property of the polymer acting through CD44 (PMID:32398747), and attributing it to the enzyme that shortens the polymer would invert the logic. Retained as peripheral, not core. Propagation Review Root cause: NO FAILURE NON CORE Supporting Evidence: PMID:32398747 vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA.
GO:0001618 virus receptor activity	IEA GO_REF:0000120	REMOVE	Summary: Jaagsiekte sheep retrovirus receptor activity is a species-idiosyncratic, multi-residue property that the only tested rodent ortholog lacks outright; the pipeline projected a positive from a donor set containing an explicitly negated donor. Reason: The positive biological argument has three parts. First, the closest tested relative is negative, not merely weaker - PMID:16191204 reports that mouse Hyal2 neither binds Env nor mediates entry, and GOA records this as an explicit NOT\|enables GO:0001618 IDA on mouse O35632. The GO_REF:0000120 WITH/FROM for this row lists that same mouse protein alongside human Q12891, so the pipeline propagated a positive assertion from a donor set that contains a curated negation for the identical term. Second, receptor competence is not a conserved family property but varies by orders of magnitude across mammals, being strong in sheep and human, weak in cattle and effectively absent in mouse. Third, it is not predictable from sequence - the determinants lie in the central third of the protein and act only in concert, with no single or double substitution accounting for more than a tenth of the difference, so no residue inspection of A0A0P6J1Y4 can license the transfer. The viruses concerned are ovine and caprine pathogens with no relationship to Heterocephalus glaber. This is a removal of an unsupported projection, not a claim that the naked mole rat protein has been shown to be non-permissive; that experiment has never been done. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:O35632 · mouse Hyal2 SOURCE BAD This donor carries a curated NOT\|enables GO:0001618 IDA from PMID:16191204 for the identical term, yet appears in the WITH/FROM of a positive projection. UniProtKB:Q12891 · human HYAL2 SUPPORTS SOURCE BUT NOT TARGET Two IDAs support the human protein, but the property is demonstrably not conserved across mammalian orthologs. Supporting Evidence: PMID:16191204 Human Hyal2 binds the envelope (Env) proteins of these viruses and is functional as a receptor, but Hyal2 from mice does not bind Env nor does it mediate entry of either virus. PMID:16191204 Mouse and human Hyal2 are 82% identical at the amino acid level but mouse Hyal2 shows 1,000-fold lower JSRV receptor activity. PMID:16191204 we previously found that bovine Hyal2 acts as a weak receptor for JSRV and ENTV compared to sheep or human Hyal2 PMID:16191204 None of the single or double mutation reduced the receptor activity of human Hyal2 by more than 10-fold, whereas mouse Hyal2 activity is reduced 1,000-fold from that of human Hyal2.
GO:0003713 transcription coactivator activity	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: A nuclear coactivator molecular function for a GPI-anchored ectoenzyme, projected from a single-laboratory reporter assay in mouse with no naked mole rat data. Reason: The sole anchor is PMID:19366691, where ectopic Hyal-2 plus WOX1 raised Smad-driven promoter activity 8-9 fold in a reporter assay. That is a real published result and the mouse IDA is not being second-guessed here, but assigning a transcription coactivator molecular function to the naked mole rat protein rests on transferring a contested moonlighting activity of a cell-surface glycosidase into a species where no aspect of it has been examined. The contributes_to qualifier is appropriately hedged, and the annotation is not deleted, but it should not be read as an established function of this protein. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: PMID:19366691 In combination, WOX1 and Hyal-2 dramatically enhanced the promoter activation (8-9-fold increases), which subsequently led to cell death
GO:0005540 hyaluronic acid binding	IEA GO_REF:0000107	ACCEPT	Summary: Substrate binding by the GH56 catalytic cleft; entailed by the demonstrated hyaluronan-degrading activity of the naked mole rat protein. Reason: Recombinant naked mole rat HYAL2 degrades hyaluronan (PMID:38052795), which requires substrate engagement, and the human donor carries two IDAs. The GH56 fold and the catalytic residue are intact in A0A0P6J1Y4. Retained as a core function alongside GO:0004415, of which it is the binding component. Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SIMILARITY: Belongs to the glycosyl hydrolase 56 family. PMID:38052795 HYAL2 hydrolyzes HMM-HA into intermediate length HA1,23, and HYAL1 further degrades small molecules of HA into tetrasaccharides24.
GO:0005737 cytoplasm	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Technically satisfiable through the endosomal and lysosomal pool but uninformative, and misleading for a protein whose functional compartment is the outer face of the plasma membrane. Reason: HYAL2 does reach endosomes and lysosomes, which are part_of cytoplasm, so the term is not false. But it conveys nothing about a GPI-anchored ectoenzyme and, read naively, suggests a cytoplasmic pool that the protein's topology forbids. The specific compartment terms already annotated (GO:0005764, GO:0030139, GO:0031410, GO:0048471) carry all of the real information. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SUBCELLULAR LOCATION: Cell membrane
GO:0005764 lysosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A genuine but secondary compartment - HYAL2 was originally described as a lysosomal enzyme, and the endocytosed pool is real, but the functionally decisive location is the cell surface. Reason: Two human IDAs support lysosomal localisation (PMID:9712871, PMID:16600643), and the acidic pH optimum of the enzyme fits a lysosomal or otherwise acidified compartment. However, the same literature subsequently established that the protein is principally a GPI-anchored cell-surface protein, and the pericellular pool is where the rate-limiting first cut of extracellular hyaluronan occurs. Kept as a real but non-core location. Supporting Evidence: PMID:11296287 HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. PMID:9712871 The HYAL2 protein was shown to have hyaluronidase activity below pH 4.
GO:0005829 cytosol	IEA GO_REF:0000107	REMOVE	Summary: Topologically incompatible with the protein's own UniProt record - a cleaved signal peptide and a GPI anchor confine the mature chain to the extracellular or luminal face. Reason: The positive argument is a topology argument, not an argument from weak evidence. A0A0P6J1Y4 is annotated with SIGNAL 1..20 and CHAIN 21..471, and with a GPI lipid anchor at the cell membrane. A protein that enters the secretory pathway and is attached to the outer leaflet by a glycolipid cannot occupy the cytosol without retrotranslocation, for which there is no evidence in any HYAL2 ortholog. The donor annotation is a single human IDA from PMID:19366691, an immunofluorescence and FRET study in which cytosolic assignment most plausibly reflects non-nuclear staining of endomembrane-associated protein. This is a judgement about the projection onto an untested species, not a re-reading of that image; the compartments the protein genuinely occupies are already annotated separately. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt SIGNAL 1..20 file:HETGA/Hyal2/Hyal2-uniprot.txt CHAIN 21..471 file:HETGA/Hyal2/Hyal2-uniprot.txt Lipid-anchor, GPI-anchor PMID:38052795 HYAL2 is a highly post-translationally modified enzyme. The first 20 amino acids of HYAL2 are predicted to be a signal sequence that directs the protein to the endoplasmic reticulum35.
GO:0005902 microvillus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A specific plasma-membrane subdomain reported for human HYAL2 by immunoelectron microscopy in one epithelial cell line; plausible for the naked mole rat but cell-type restricted. Reason: The human IDA comes from PMID:19366691, which localised Hyal-2 to microvilli in HCT116 cells by immunoelectron microscopy. Microvillar enrichment is a normal behaviour of GPI-anchored raft proteins in polarised epithelia, so the transfer is mechanistically reasonable, but it is a cell-type-specific refinement of the plasma-membrane location rather than a general property. Supporting Evidence: PMID:19366691 we determined that TGF-beta1 bound cell surface hyaluronidase Hyal-2 on microvilli in type II TGF-beta receptor-deficient HCT116 cells, as determined by immunoelectron microscopy.
GO:0006027 glycosaminoglycan catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: The correct parent process. Hyaluronan is a glycosaminoglycan and the enzyme degrades it; the informative child GO:0030214 is separately annotated. Reason: Supported by a human IDA (PMID:9712871) and true of the naked mole rat protein, whose hyaluronan-degrading activity has been demonstrated directly (PMID:38052795). It is broader than GO:0030214, which is also present in this set, but a correct parent alongside its child is not an error and requires no modification. Supporting Evidence: PMID:38052795 HYAL2 hydrolyzes HMM-HA into intermediate length HA1,23, and HYAL1 further degrades small molecules of HA into tetrasaccharides24.
GO:0009615 response to virus	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: Rests entirely on the jaagsiekte sheep retrovirus receptor story, which does not transfer to this species; the term is broader than that story and so is flagged rather than removed. Reason: Both human IDAs for this term (PMID:11296287, PMID:12676986) are JSRV entry and Env-transformation experiments. With the underlying receptor activity annotation removed for this species, the mechanistic basis for a viral response role disappears. Unlike GO:0001618 and GO:0046718, however, response to virus is a broad process term that is not itself contradicted by the mouse data, so it is marked over-annotated rather than removed. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:12676986 The candidate tumor-suppressor gene hyaluronidase 2 (HYAL2) encodes a glycosylphosphatidylinositol-anchored cell-surface protein that serves as an entry receptor for jaagsiekte sheep retrovirus
GO:0009897 external side of plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: The exact topological consequence of GPI anchoring, and the compartment in which the enzyme meets extracellular hyaluronan. Reason: The mature chain is tethered to the outer leaflet by a glycolipid anchor, so the catalytic domain faces the extracellular space; this is what makes HYAL2 the enzyme that performs the first cut on matrix hyaluronan. Four human IDAs support the location. The colocalizes_with qualifier is a reasonable hedge for a GPI-anchored protein that also cycles through endosomes. Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt Lipid-anchor, GPI-anchor PMID:33846452 The principal somatic HA-depolymerizing enzymes, i.e. hyaluronidases, are HYAL1 and HYAL2. HA is degraded at the cell surface by the glycosylphosphatidylinositol (GPI)-linked HYAL2 into intermediate-size fragments.
GO:0009986 cell surface	IEA GO_REF:0000120	ACCEPT	Summary: The defining localisation of HYAL2 as distinct from lysosomal HYAL1, and the site of its rate-limiting activity. Reason: Supported by a human IDA and an ISS, a mouse IDA, and the GPI anchor annotated directly on the naked mole rat record. The functional significance is that the cell-surface pool is what encounters extracellular high-molecular-mass hyaluronan and produces the intermediate fragments that HYAL1 then finishes. Supporting Evidence: PMID:11296287 HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SUBCELLULAR LOCATION: Cell membrane
GO:0010764 negative regulation of fibroblast migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A downstream cellular consequence of pericellular hyaluronan trimming, reported for human HYAL2; peripheral to the enzyme's core activity. Reason: The human donor has a single IDA (PMID:19577615). Mechanistically it is a plausible consequence of stripping the hyaluronan-rich glycocalyx and uncoupling CD44 from the ERM cytoskeleton, so the transfer is not unreasonable, but it is a cell-behaviour readout two steps downstream of the molecular function and has never been examined in the naked mole rat. Propagation Review Root cause: NO FAILURE NON CORE
GO:0016324 apical plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A polarity-specific refinement of the plasma-membrane location observed in one human epithelial system; genuine but cell-type restricted. Reason: Human IDA from PMID:20554532. Apical enrichment is expected for a GPI-anchored raft protein in polarised epithelia and is consistent with the microvillar localisation annotated separately, but it is a context-dependent subdomain rather than a general property of the protein, and no naked mole rat tissue has been examined. Propagation Review Root cause: NO FAILURE NON CORE
GO:0019899 enzyme binding	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: An uninformative binding term whose only anchor is the WWOX interaction; it carries no functional content. Reason: The human and mouse anchors are both the WWOX/WOX1 co-immunoprecipitation in PMID:19366691, and the term is generic enough to be satisfied by almost any protein interaction. It tells a reader nothing about what this protein does, which is precisely the failure mode the curation guidance warns against for protein binding and its near relatives. The specific interactions worth recording are already captured by GO:0030971 for RON/MST1R and GO:0050431 for TGF-beta1. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: PMID:19366691 This binding resulted in recruitment of proapoptotic WOX1 (also named WWOX or FOR) and formation of Hyal-2.WOX1 complexes for relocation to the nuclei.
GO:0030139 endocytic vesicle	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Part of the normal itinerary of a cell-surface enzyme whose products are internalised for lysosomal completion; real but secondary. Reason: Human IDA from PMID:19366691. The two-step model of hyaluronan catabolism requires that HYAL2-generated fragments be endocytosed and delivered to lysosomes, so an endocytic-vesicle pool of the enzyme is expected. It is a trafficking compartment rather than the site where the rate-limiting extracellular cut occurs. Supporting Evidence: PMID:33846452 The principal somatic HA-depolymerizing enzymes, i.e. hyaluronidases, are HYAL1 and HYAL2. HA is degraded at the cell surface by the glycosylphosphatidylinositol (GPI)-linked HYAL2 into intermediate-size fragments.
GO:0030214 hyaluronan catabolic process	IEA GO_REF:0000120	ACCEPT	Summary: The core biological process. Directly demonstrated for the naked mole rat protein, which degrades hyaluronan when expressed in cultured cells. Reason: Naked mole rat HYAL2 degrades hyaluronan in transfected HeLa and HEK293T cells (PMID:38052795), and the naked mole rat is one of the species in which the balance of hyaluronan synthesis against degradation is under documented selection. The donor support is unusually strong - a PANTHER node (PTN000205964), five human IDAs, two mouse IMPs and an IBA. Note that the process is attenuated rather than lost in this species; the enzyme is weaker at G284 than the ancestral form, but weakening a rate is not the same as abolishing a process. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:38052795 A positively selected site G284 was also identified in NMR and DMR HYAL2 (Fig. 3c). We tested the effect of this mutation on NMR HYAL2. We did not observe difference when HA was incubated for two days, but the size and amount of HA was smaller after three days of incubation (Fig. 5i), suggesting that the substitution in G284 also contributes to the weaker HYAL2 in NMRs. PMID:38052795 All the positively selected sites are located in the GHF domain, which is responsible for the hydrolase activity and HA degradation. file:HETGA/Hyal2/Hyal2-uniprot.txt Essential for the breakdown of extracellular matrix hyaluronan.
GO:0030294 receptor signaling protein tyrosine kinase inhibitor activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The RON/MST1R silencing activity - a real second function of HYAL2, corroborated on the naked mole rat record by the UniProt MST1R interaction, but untested in this species and unrelated to hyaluronan catabolism. Reason: Human IDA from PMID:12676986, which showed that HYAL2 holds RON functionally silent and that releasing it activates AKT and MAPK signalling. UniProt records an MST1R interaction directly on A0A0P6J1Y4 (ARBA), so the scaffold role is at least asserted for this protein. RON/MST1R is broadly conserved in mammals, making the transfer more defensible than the JSRV receptor transfer, but it remains an unexamined moonlighting function in the naked mole rat and is not part of the core hyaluronidase role. Supporting Evidence: PMID:12676986 the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SUBUNIT: Interacts with MST1R.
GO:0030308 negative regulation of cell growth	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A tumour-suppressor-flavoured phenotype term from a single human IDA; peripheral and, in the naked mole rat, arguably pointing the wrong way. Reason: Human IDA from PMID:18725949, consistent with the historical description of HYAL2 as a candidate lung-cancer tumour suppressor. Worth flagging that in the naked mole rat the growth-suppressive signal runs through very-high-molecular-mass hyaluronan binding CD44, and that overexpressing a HYAL2 in naked mole rat cells removes that suppression and permits tumour formation; if anything, more HYAL2 activity is permissive for growth in this species. Kept as a non-core annotation rather than being contradicted, because the human result concerns a different mechanism. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:23783513 naked mole-rat cells expressing H-Ras V12 and SV40 LT and shRNA to HAS2 or overexpressing Hyal2 formed tumors in mice
GO:0030971 receptor tyrosine kinase binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Binding to RON/MST1R, asserted for this protein by UniProt and supported by a human IPI; the binding counterpart of GO:0030294. Reason: Human IPI from PMID:12676986, and UniProt annotates the MST1R interaction directly on the naked mole rat entry. More informative than a bare protein binding term because it names the class of partner, but still a peripheral scaffold role rather than the protein's core activity, and never tested in this species. Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SUBUNIT: Interacts with MST1R. PMID:12676986 the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: The parent of the endocytic-vesicle location, carried on a PANTHER node with an is_active_in IBA in human; a real trafficking compartment, less informative than its child. Reason: Supported by a PANTHER node (PTN000205964) and by human IDAs plus an IBA that uses is_active_in. GO:0030139 endocytic vesicle, also present in this set, is the informative form. Retained as a non-core trafficking location. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH
GO:0032755 positive regulation of interleukin-6 production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Part of the pro-inflammatory signalling attributed to HYAL2-generated low-molecular-mass hyaluronan fragments; peripheral to the enzyme itself. Reason: Human IDA from PMID:19443707. The mechanism is indirect - short hyaluronan fragments produced by hyaluronidase action are the pro-inflammatory species - so the process depends on the catalytic activity but is not itself a function of the protein. Untested in the naked mole rat, where the intact very-high-molecular-mass polymer is anti-inflammatory. Propagation Review Root cause: NO FAILURE NON CORE
GO:0032757 positive regulation of interleukin-8 production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Same fragment-driven inflammatory mechanism as the IL-6 term, and taxonomically applicable here because Heterocephalus glaber does retain a Cxcl8 gene. Reason: Human IDA from PMID:19443707. Interleukin-8/CXCL8 terms are often inapplicable to rodent projections because murid rodents lack a CXCL8 ortholog, so this was checked - UniProt records a Cxcl8 gene for Heterocephalus glaber (A0A0P6JFD0), as it does for guinea pig and other hystricomorphs, so the term is not taxonomically excluded in this species. Kept as non-core on the same indirect, fragment-mediated grounds as GO:0032755. Propagation Review Root cause: NO FAILURE NON CORE
GO:0033906 hyaluronoglucuronidase activity	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: EC 3.2.1.36, a different bond specificity from the EC 3.2.1.35 activity that defines mammalian HYAL2 and that UniProt assigns to this protein. Reason: GO:0033906 is hydrolysis of beta-1,3 linkages between glucuronate and N-acetylglucosamine, the leech and hookworm type mechanism, whereas GO:0004415 is the beta-1,4 endo-hexosaminidase mechanism of mammalian hyaluronidases. The two describe mutually exclusive cleavage chemistries. UniProt assigns A0A0P6J1Y4 EC 3.2.1.35 and only that, on RuleBase evidence. The donor support is correspondingly lopsided - nine human IDAs for GO:0004415 against one IDA plus a PANTHER IBA for GO:0033906. The linkage specificity of the naked mole rat enzyme has never been determined, so this is flagged rather than removed, but it should not be treated as a second established activity. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt EC=3.2.1.35 file:HETGA/Hyal2/Hyal2-uniprot.txt Random hydrolysis of (1->4)-linkages between N-acetyl-beta-D-
GO:0042117 monocyte activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Immune-cell phenotype from the same human study as the cytokine terms; downstream of hyaluronan fragment generation and untested here. Reason: Human IDA from PMID:19443707. Consistent with the established immunological role of short hyaluronan fragments, which are recognised as danger signals, but it is a cellular outcome several steps removed from the molecular function and has no naked mole rat support. Propagation Review Root cause: NO FAILURE NON CORE
GO:0042307 positive regulation of protein import into nucleus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Part of the WWOX nuclear-relocation module from one mouse study; a strong claim for a GPI-anchored ectoenzyme, with no evidence in this species. Reason: Mouse IDA from PMID:19366691, where Hyal-2/WOX1 complexes were reported to relocate to the nucleus. The claim is that a cell-surface glycosidase promotes nuclear import of a partner, which requires the whole contested translocation model to be correct. That model has not been reproduced outside its originating laboratory and has never been examined in the naked mole rat, so the projection is flagged. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Supporting Evidence: PMID:19366691 This binding resulted in recruitment of proapoptotic WOX1 (also named WWOX or FOR) and formation of Hyal-2.WOX1 complexes for relocation to the nuclei.
GO:0044344 cellular response to fibroblast growth factor stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Companion term to the fibroblast-migration annotation from the same human study; a signalling-context readout rather than a function. Reason: Human IDA from PMID:19577615, the same study that grounds GO:0010764. Retained as peripheral context. Nothing is known about FGF responsiveness of naked mole rat Hyal2. Propagation Review Root cause: NO FAILURE NON CORE
GO:0045121 membrane raft	IEA GO_REF:0000120	ACCEPT	Summary: Raft partitioning is the expected and experimentally confirmed consequence of GPI anchoring, and is where the pericellular enzyme sits. Reason: Human and mouse both carry IDAs from PMID:21740893, which demonstrated GPI anchoring by PI-PLC release and Triton X-114 partitioning and showed association with detergent-resistant cholesterol-rich fractions. The human record additionally has an is_active_in IDA, marking the raft as a site of function rather than mere residence. The GPI anchor is annotated on the naked mole rat record itself, so the structural basis for the transfer is present in this protein. Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt Lipid-anchor, GPI-anchor file:HETGA/Hyal2/Hyal2-deep-research-affinage-human-ortholog.md Hyal2 is specifically associated with detergent-resistant, cholesterol-rich lipid raft membrane fractions.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: The transcriptional output of the WWOX module, from a reporter assay in one mouse study; over-reach for a GPI-anchored ectoenzyme in an untested species. Reason: Mouse IDA from PMID:19366691, based on an 8-9-fold increase in Smad-driven promoter activity when Hyal-2 and WOX1 were co-expressed. Promoter-reporter activation by co-overexpression is a weak basis for asserting that a cell-surface hydrolase positively regulates Pol II transcription, and there is no naked mole rat evidence of any kind. Flagged, not removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Supporting Evidence: PMID:19366691 In combination, WOX1 and Hyal-2 dramatically enhanced the promoter activation (8-9-fold increases), which subsequently led to cell death
GO:0046677 response to antibiotic	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Derived from a human expression-pattern observation (IEP) in cultured cells; a pharmacological response rather than a biological function, and meaningless for a wild subterranean rodent. Reason: The human anchor is an IEP from PMID:11944887 - a change in transcript level after a chemical treatment, which is the weakest evidence class for a process annotation and does not establish that the gene product participates in a response. Projecting that observation across species produces an assertion about naked mole rat physiology that no experiment has addressed and that has no plausible ecological counterpart. Flagged rather than removed only because the annotation is not biologically contradicted, merely unsupported. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q12891 · human HYAL2 SOURCE WEAK OR INFERRED Sole support is an IEP (expression pattern) from PMID:11944887.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Imaging-derived compartment for the internalised pool of human HYAL2; real but secondary and not examined in this species. Reason: Human IDA from PMID:16600643. Perinuclear accumulation is consistent with the late endosomal and lysosomal pool of an endocytosed cell-surface enzyme, which is separately annotated. Retained as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE
GO:0050431 transforming growth factor beta binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The ligand-binding end of the TGF-beta1 and WWOX module, supported by a mouse IPI; a specific and testable claim, unlike the nuclear end of the same module. Reason: Mouse IPI from PMID:19366691, which mapped the interaction to the catalytic domain of Hyal-2. TGF-beta1 and its receptors are highly conserved, so a cell-surface binding interaction is a more transferable claim than the downstream transcriptional assertions from the same paper, which is why this is kept as non-core while GO:0003713, GO:0090575, GO:0045944 and GO:0042307 are marked over-annotated. No naked mole rat data exist. Supporting Evidence: PMID:19366691 we determined that TGF-beta1 bound cell surface hyaluronidase Hyal-2 on microvilli in type II TGF-beta receptor-deficient HCT116 cells, as determined by immunoelectron microscopy.
GO:0050729 positive regulation of inflammatory response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The umbrella term for the fragment-driven inflammatory cluster; retained as peripheral. Reason: Human IDA from PMID:19443707, the same study behind the IL-6, IL-8 and monocyte-activation terms. Indirect, mediated by the size of the hyaluronan fragments the enzyme produces rather than by the protein itself, and untested in the naked mole rat. Propagation Review Root cause: NO FAILURE NON CORE
GO:0051216 cartilage development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A developmental role with genuine mammalian genetic support from Hyal2-null mice and human HYAL2 patients, though the human GO anchor is only an expression-pattern observation. Reason: The human donor annotation is an IEP from PMID:11944887, which alone would be weak. The transfer is nevertheless defensible because independent genetic evidence exists in mammals - Hyal2-deficient mice have localised congenital defects in frontonasal and vertebral bone formation, and biallelic human HYAL2 loss causes syndromic orofacial clefting. This is exactly the pleiotropic developmental role the curation guidance directs to be kept as non-core; it is real for the family, it is not the enzyme's core function, and it has never been examined in the naked mole rat. Propagation Review Root cause: NO FAILURE NON CORE Supporting Evidence: PMID:18772348 They exhibit localized congenital defects in frontonasal and vertebral bone formation and suffer from mild thrombocytopenia and chronic, possibly intravascular, hemolysis.
GO:0051607 defense response to virus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Mouse IDA drawn from the jaagsiekte sheep retrovirus receptor study; entirely specific to an ovine pathogen with no relationship to this species. Reason: The mouse anchor is an IDA from PMID:16191204, the study whose principal finding is that mouse Hyal2 does not function as a JSRV receptor. Whatever antiviral role the curator read into that work, it is framed entirely by JSRV and ENTV biology. The same paper reports no evidence that mammalian hosts have evolved Hyal2 changes to resist these viruses, which further undercuts a general defence role. Flagged rather than removed because defense response to virus is a broad process term that the data do not directly contradict. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:16191204 Together these results provide strong evidence for conservation of Hyal2 protein sequence but no evidence for positive selection to resist virus infection.
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The signalling consequence of holding RON/MST1R silent; the process partner of GO:0030294 and GO:0030971. Reason: Human IDA from PMID:12676986, where release of RON from HYAL2 activates AKT and MAPK, implying that the bound state suppresses that signalling. Coherent with the two other RON-module annotations and corroborated at the interaction level by the UniProt MST1R line on this record, but a peripheral regulatory role rather than the enzyme's core activity, and unexamined in the naked mole rat. Supporting Evidence: PMID:12676986 RON liberated from the association with HYAL2 becomes functionally active and consequently activates the Akt and mitogen-activated protein kinase pathways leading to oncogenic transformation of immortalized human bronchial epithelial cells.
GO:0071347 cellular response to interleukin-1	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cytokine-responsiveness of HYAL2 expression or activity in human cells; a regulatory-context annotation, kept as peripheral. Reason: Human IDA from PMID:18390475. Inflammatory cytokine regulation of hyaluronidase expression is a recurring theme in the field and is mechanistically plausible in any mammal, but it describes how the gene is controlled rather than what the protein does, and no naked mole rat experiment bears on it. Propagation Review Root cause: NO FAILURE NON CORE
GO:0071356 cellular response to tumor necrosis factor	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Same regulatory-context class as the IL-1 term, but resting on an expression-pattern observation rather than a direct assay. Reason: The human anchor is an IEP from PMID:18390475, weaker than the IDA behind the IL-1 term. Retained as peripheral context on the strength of the coherent cytokine-regulation picture across that study, while noting that expression-pattern evidence alone would not support a process annotation on its own. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: SOURCE EVIDENCE WEAK
GO:0071493 cellular response to UV-B	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: A skin photobiology term projected onto a hairless, obligately subterranean animal that is essentially never exposed to solar UV-B. Reason: Human IDA from PMID:21699545, a keratinocyte UV-B study. This is the clearest case in the set of an organism-physiology term whose stimulus does not occur in the target species. Heterocephalus glaber lives underground and its skin never encounters meaningful solar UV-B, so the annotation asserts participation in a response that has no ecological realisation. It is flagged rather than removed because GO response terms describe a capacity, and the cellular machinery downstream of UV damage is conserved, so the naked mole rat protein might well respond if artificially irradiated. But it should not be read as part of this gene's biology. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH LINEAGE OR TAXON MISMATCH
GO:0071560 cellular response to transforming growth factor beta stimulus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: The response counterpart of the TGF-beta1 binding annotation; supported by IDAs in both human and mouse, but peripheral to hyaluronan catabolism. Reason: Human and mouse both carry IDAs from PMID:19366691. Together with GO:0050431 this is the defensible half of the TGF-beta module - a ligand binding at the cell surface and a cellular response to that ligand, both conserved-plausible - as distinct from the nuclear coactivator claims, which are marked over-annotated. No naked mole rat data. Supporting Evidence: PMID:19366691 we determined that TGF-beta1 bound cell surface hyaluronidase Hyal-2 on microvilli in type II TGF-beta receptor-deficient HCT116 cells, as determined by immunoelectron microscopy.
GO:0090575 RNA polymerase II transcription regulator complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Asserts that a GPI-anchored cell-surface hydrolase is a structural part of a transcription factor complex - the strongest claim in the WWOX module and the least supported. Reason: The mouse anchor is an IDA and the human anchor an ISS, both tracing to PMID:19366691. A part_of assertion into a transcription regulator complex is a structural claim about stable complex membership, and the underlying data are FRET, co-immunoprecipitation and promoter reporters in one laboratory, with no complex purification. For a protein whose own UniProt record places it in the cell membrane on a GPI anchor, projecting that membership into an untested species is the least defensible cellular-component annotation in this set. Flagged rather than removed, because the mouse experimental annotation itself is not being overruled. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: COMPARTMENT OR COMPLEX MISMATCH ROLE CONFLATION Supporting Evidence: file:HETGA/Hyal2/Hyal2-uniprot.txt -!- SUBCELLULAR LOCATION: Cell membrane PMID:19366691 In combination, WOX1 and Hyal-2 dramatically enhanced the promoter activation (8-9-fold increases), which subsequently led to cell death

Gene Description

Proposed New Ontology Terms

regulation of hyaluronan polymer size

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Affinage

Falcon

📚 Additional Documentation

Notes

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