Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0043066 negative regulation of apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference that HYPK negatively regulates apoptosis, a process downstream of its chaperone/anti-aggregation activity. Reason: Documented experimentally and by family inference but a downstream consequence of HYPK's chaperone role rather than its core molecular function. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0043066 negative regulation of apoptotic process biological_process IDA PMID:17947297
GO:0050821 protein stabilization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference that HYPK stabilizes proteins, consistent with its anti-aggregation chaperone activity. Reason: A plausible biological-process outcome of HYPK's chaperone function; retained as non-core relative to the chaperone MF. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0050821 protein stabilization biological_process IDA PMID:17947297
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic annotation of nuclear localization, consistent with the documented nuclear pool of HYPK. Reason: Nuclear pool documented; HYPK's core NatA-associated/chaperone role is cytoplasmic/ribosome-associated, so nuclear localization is non-core. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005634 nucleus cellular_component EXP PMID:20154145
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of cytoplasmic localization, the principal site of HYPK's NatA-associated and chaperone activity. Reason: Cytoplasm is the main site of HYPK function; well supported. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005737 cytoplasm cellular_component EXP PMID:20154145
GO:0006457 protein folding	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Inferred from the protein-folding-chaperone MF; HYPK participates in protein folding/quality control as a chaperone. Reason: A reasonable process annotation downstream of HYPK's chaperone MF; kept non-core. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
GO:0005515 protein binding	IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu...	KEEP AS NON CORE	Summary: IntAct interaction with HTT (P42858, huntingtin), the namesake client of HYPK. Generic protein binding term. Reason: Records the functionally important HYPK-HTT interaction; informative function (chaperone) captured elsewhere. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:17500595 UniProtKB:P42858
GO:0005515 protein binding	IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme...	KEEP AS NON CORE	Summary: IntAct interaction with NAA15 (Q9BXJ9), HYPK's principal NatA-complex partner. Generic protein binding term. Reason: Records the central HYPK-NAA15 interaction underlying NatA/HYPK complex formation; informative function captured elsewhere. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:24981860 UniProtKB:Q9BXJ9
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale yeast two-hybrid interactome (e.g. P40222, P43355). Bare protein binding term. Reason: High-throughput interactome data; uninformative as a core MF. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:25416956 UniProtKB:P40222
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: IntAct interaction with NAA15 (Q9BXJ9). Generic protein binding term. Reason: Records the central HYPK-NAA15 interaction; informative function captured elsewhere. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:28514442 UniProtKB:Q9BXJ9
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: High-throughput interactome capturing NAA15 (Q9BXJ9) and other partners. Generic protein binding term. Reason: Records real interactions including HYPK-NAA15; generic MF kept non-core. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:32296183 UniProtKB:Q9BXJ9
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegeneration interactome capturing the HYPK-HTT (P42858) interaction. Generic protein binding term. Reason: Records the HYPK-HTT interaction; informative function captured elsewhere. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:32814053 UniProtKB:P42858
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex interactome capturing NAA15 (Q9BXJ9). Generic protein binding term. Reason: Records the HYPK-NAA15 interaction; generic MF kept non-core. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:33961781 UniProtKB:Q9BXJ9
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-maps interactome capturing NAA15 (Q9BXJ9). Generic protein binding term. Reason: Records the HYPK-NAA15 interaction; generic MF kept non-core. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:40205054 UniProtKB:Q9BXJ9
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence nucleoplasmic localization, consistent with the documented nuclear pool of HYPK. Reason: Nuclear pool documented; non-core relative to cytoplasmic NatA-associated function. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005654 nucleoplasm cellular_component IDA GO_REF:0000052 HPA
GO:0005634 nucleus	EXP PMID:20154145 The chaperone-like protein HYPK acts together with NatA in c...	KEEP AS NON CORE	Summary: Experimental nuclear localization of HYPK. Reason: Documented nuclear pool; non-core relative to cytoplasmic function. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005634 nucleus cellular_component EXP PMID:20154145
GO:0005737 cytoplasm	EXP PMID:20154145 The chaperone-like protein HYPK acts together with NatA in c...	ACCEPT	Summary: Experimental cytoplasmic localization, the principal site of HYPK function. Reason: Core localization for HYPK's NatA-associated and chaperone roles. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005737 cytoplasm cellular_component EXP PMID:20154145
GO:0044183 protein folding chaperone	EXP PMID:18076027 Huntingtin interacting protein HYPK is intrinsically unstruc...	ACCEPT	Summary: Experimental evidence (DisProt) that the intrinsically disordered HYPK acts as a chaperone preventing aggregation of clients; the core molecular function. Reason: Direct experimental evidence for HYPK's chaperone activity; this is its core, informative non-catalytic MF. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
GO:0044183 protein folding chaperone	IDA PMID:18076027 Huntingtin interacting protein HYPK is intrinsically unstruc...	ACCEPT	Summary: Direct experimental evidence for HYPK chaperone activity; core MF. Reason: Direct experimental support for the core chaperone function. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
GO:0005515 protein binding	IPI PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	KEEP AS NON CORE	Summary: IntAct interaction with HTT (P42858); the original HYPK-huntingtin interaction underpinning its anti-polyQ-aggregation activity. Generic protein binding term. Reason: Records the functionally central HYPK-HTT interaction; informative chaperone function captured elsewhere. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:17947297 UniProtKB:P42858
GO:0005634 nucleus	IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	KEEP AS NON CORE	Summary: Direct nuclear localization of HYPK. Reason: Documented nuclear pool; non-core relative to cytoplasmic function. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005634 nucleus cellular_component IDA PMID:17947297
GO:0005737 cytoplasm	IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	ACCEPT	Summary: Direct cytoplasmic localization of HYPK. Reason: Core localization for HYPK function. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0005737 cytoplasm cellular_component IDA PMID:17947297
GO:0032991 protein-containing complex	IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	KEEP AS NON CORE	Summary: HYPK is part of a protein complex; this is captured more precisely by its membership in the NatA/HYPK complex. Reason: Generic complex term; HYPK's specific complex is the NatA/HYPK complex, so this high-level CC term is retained non-core. Recent cryo-EM-based synthesis places this HYPK-NatA assembly on translating ribosomes near the polypeptide exit tunnel together with NAC and the methionine aminopeptidases. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Component of the N-terminal acetyltransferase A (NatA)/HYPK complex at least composed of NAA10, NAA15 and HYPK file:human/HYPK/HYPK-deep-research-falcon.md HYPK can be detected in ribosomal complexes that include NatA, the nascent polypeptide-associated complex (NAC), and methionine aminopeptidases (MAP1 or MAP2)
GO:0043066 negative regulation of apoptotic process	IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	KEEP AS NON CORE	Summary: Direct evidence that HYPK negatively regulates apoptosis, downstream of its anti-aggregation chaperone activity. Reason: A documented downstream process; non-core relative to the chaperone MF. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0043066 negative regulation of apoptotic process biological_process IDA PMID:17947297
GO:0050821 protein stabilization	IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	KEEP AS NON CORE	Summary: Direct evidence that HYPK stabilizes proteins (suppressing aggregation), a process outcome of its chaperone activity. Reason: Documented downstream process; non-core relative to the chaperone MF. Supporting Evidence: file:human/HYPK/HYPK-goa.tsv GO:0050821 protein stabilization biological_process IDA PMID:17947297

Core Functions

Intrinsically disordered, ribosome/NatA-associated chaperone that suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine aggregation of N-terminal huntingtin, acting in association with the NatA complex.

Molecular Function:

protein folding chaperone

Cellular Locations:

cytoplasm

Supporting Evidence:

file:human/HYPK/HYPK-uniprot.txt
Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells

Non-catalytic regulatory subunit of the NatA/HYPK N-terminal acetyltransferase complex that binds NAA15 and reduces (inhibits) the N-terminal acetyltransferase activity of the NAA10-NAA15 (NatA) complex and modulates its interaction with NAA50.

Molecular Function:

enzyme inhibitor activity

In Complex:

NatA complex

Supporting Evidence:

file:human/HYPK/HYPK-uniprot.txt
Inhibits the N-terminal acetylation activity of the N-terminal acetyltransferase NAA10-NAA15 complex (also called the NatA complex)
file:human/HYPK/HYPK-deep-research-falcon.md
HYPK inhibits the catalytic activity of NAA10 through an allosteric mechanism.
file:human/HYPK/HYPK-deep-research-falcon.md
HYPK binding has a strong stabilizing effect on the NatA complex

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000108

Gene Ontology annotation based on inference from GO term-to-term logical definitions

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:17500595

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

PMID:17947297

HYPK, a Huntingtin interacting protein, reduces aggregates and apoptosis induced by N-terminal Huntingtin with 40 glutamines in Neuro2a cells and exhibits chaperone-like activity.

HYPK interacts with N-terminal huntingtin, exhibits chaperone-like activity reducing polyQ aggregates and apoptosis, and localizes to cytoplasm and nucleus.

PMID:18076027

Huntingtin interacting protein HYPK is intrinsically unstructured.

HYPK is intrinsically unstructured and possesses chaperone-like anti-aggregation activity.

PMID:20154145

The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation.

HYPK is a stable component of the NatA complex (with NAA10 and NAA15), and the NatA complex is required for HYPK stability and for reducing polyQ aggregation of HTT.

PMID:24981860

Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.

HYPK interacts with NAA15 within the NatA/HYPK complex.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/HYPK/HYPK-deep-research-falcon.md

Falcon deep research report for HYPK

HYPK is a non-catalytic regulator of the NatA (NAA10-NAA15) complex that stabilizes the complex and allosterically inhibits NAA10; it is ribosome/polysome-associated near the exit tunnel together with NatA, NAC and MAP1/MAP2.
HYPK additionally functions as a selective autophagy receptor that bridges polyneddylated protein cargo (via its C-terminal UBA domain binding NEDD8) to LC3/GABARAP autophagosomal proteins (via an atypical N-terminal LIR), per Ghosh & Ranjan 2022.

Suggested Experiments

Experiment: In vitro reconstitution measuring NatA N-terminal acetyltransferase activity with and without HYPK and NAA50 to quantify HYPK's inhibitory effect and its competition with NAA50.

Experiment: Aggregation assays (FRAP, filter-trap) of expanded-polyQ HTT in cells with HYPK knockout versus HYPK reconstituted in NatA-binding-deficient form to test whether chaperone activity requires NatA association.

Experiment: Selective ribosome profiling / N-terminal acetylome comparison upon HYPK depletion to define which nascent-chain substrates are co-regulated by HYPK and NatA.

Deep Research

Falcon

(HYPK-deep-research-falcon.md)

Comprehensive Research Report: HYPK (Huntingtin-Interacting Protein K) Falcon Edison Scientific Literature 26 citations 1 artifacts 2026-06-20T07:16:44.001055

Edison artifact artifact-00 (text/markdown)

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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: HYPK (Huntingtin-Interacting Protein K)

Gene and Protein Identity

HYPK (UniProt accession: Q9NX55) encodes Huntingtin-interacting protein K, also known as huntingtin yeast partner K, in humans (Homo sapiens). The gene is located on chromosome 15 (synonyms: C15orf63, HSPC136) and belongs to a conserved family of regulatory proteins involved in co-translational protein processing and proteostasis (liu2023huntingtininteractingproteins pages 1-2, liu2023huntingtininteractingproteins pages 2-4).

Primary Molecular Functions

HYPK exhibits dual, mechanistically distinct molecular functions that have been elucidated through recent structural and biochemical studies:

1. Regulatory Component of the NatA N-Terminal Acetyltransferase Complex

HYPK functions as a non-catalytic regulatory subunit of the NatA complex, which is responsible for N-terminal acetylation of up to 40-50% of mammalian proteins (deng2021proteinnterminalacetylation pages 2-3, damme2021chartingthenterminal pages 1-2). The NatA complex comprises the catalytic subunit NAA10 and the large ribosome-anchoring auxiliary subunit NAA15. HYPK physically associates with this NatA heterodimer and exerts two key regulatory effects:

Stabilization: HYPK binding has a strong stabilizing effect on the NatA complex, promoting proper assembly and maintenance of the NAA10-NAA15 heterodimer (deng2021proteinnterminalacetylation pages 2-3, klein2024multiproteinassembliesorchestrate pages 2-3).

Catalytic Inhibition: HYPK inhibits the catalytic activity of NAA10 through an allosteric mechanism. Structural studies demonstrate that HYPK binding to the NAA15 α-helical scaffold induces conformational rearrangements in the first two tetratricopeptide repeat (TPR) motifs of NAA15. This bending occurs in the opposite direction compared to ribosome-bound NatA, indicating structural plasticity (klein2024multiproteinassembliesorchestrate pages 2-3). These rearrangements allosterically inhibit NAA10 and can also prevent NAA50 (a component of the NatE complex) from binding to NatA (deng2021proteinnterminalacetylation pages 2-3, damme2021chartingthenterminal pages 1-2).

Coordination of Co-Translational Processing: Recent cryo-EM structures from 2024 reveal that HYPK participates in organizing multi-protein assemblies at the ribosome exit tunnel for coordinated nascent chain processing (klein2024multiproteinassembliesorchestrate pages 1-2, lentzsch2024nacguidesa pages 1-9). HYPK can be detected in ribosomal complexes that include NatA, the nascent polypeptide-associated complex (NAC), and methionine aminopeptidases (MAP1 or MAP2), supporting a model in which HYPK helps tune the assembly states of co-translational processing machinery (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3).

It is important to note that HYPK is a regulatory protein, not an enzyme with intrinsic substrate specificity. Rather, it modulates the activity of NatA, which acetylates protein N-termini starting with small, uncharged amino acids (Ser, Ala, Gly, Thr, Val, Cys) after initiator methionine removal (damme2021chartingthenterminal pages 1-2).

2. Selective Autophagy Receptor for Polyneddylated Protein Aggregates

In a functionally independent role, HYPK serves as an autophagy receptor that mediates the selective degradation of polyneddylated proteins during proteotoxic stress (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 2-4).

NEDD8 Recognition: HYPK binds to the ubiquitin-like protein NEDD8 through its C-terminal ubiquitin-associated (UBA) domain. Biochemical analyses including surface plasmon resonance and immunoprecipitation demonstrate that HYPK binds both monomeric NEDD8 and polyneddylated chains formed on misfolded or aggregated proteins (ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 8-10). Critical conserved residues in the UBA domain—aspartate-94 (D94), glutamate-101 (E101), leucine-113 (L113), and glycine-118 (G118)—are required for efficient NEDD8 binding, with E101 and G118 positioned for direct interaction and D94 and L113 stabilizing the UBA fold (ghosh2022hypkcoordinatesdegradation pages 8-10).

LC3/GABARAP Interaction: HYPK contains an atypical tyrosine-type LC3-interacting region (LIR) motif with the sequence Y49AEE52 in its N-terminal region (ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10). This motif differs from canonical LIR sequences by having an acidic amino acid (glutamate) at the fourth position instead of a hydrophobic residue. Mutational analysis and binding assays confirm that this region mediates direct interaction with LC3A, LC3B, GABARAP, GABARAPL1, and GABARAPL2—members of the ATG8 family that decorate autophagosomal membranes (ghosh2022hypkcoordinatesdegradation pages 10-11).

Scaffolding Function in Aggrephagy: By simultaneously binding NEDD8-modified cargo through its UBA domain and autophagosomal LC3/GABARAP proteins through its LIR, HYPK functions as a molecular scaffold that bridges polyneddylated protein aggregates to the autophagy machinery (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10). This scaffolding activity is analogous to the well-characterized ubiquitin-LC3 bridging performed by SQSTM1/p62 in ubiquitin-dependent autophagy, but operates in a NEDD8-specific pathway.

Autophagy Modulation: Beyond cargo recognition, HYPK positively modulates autophagy flux. HYPK depletion reduces LC3B lipidation, autophagosome formation, and autolysosome maturation, whereas HYPK overexpression increases these parameters (ghosh2022hypkcoordinatesdegradation pages 10-11). HYPK knockdown also reduces phosphorylation of BECN1 at serine-15, a key autophagy initiation signal (ghosh2022hypkcoordinatesdegradation pages 2-4). Thus, HYPK not only recruits cargo but also promotes autophagy induction and maturation.

Protein Structure and Domains

HYPK possesses a tripartite domain architecture that supports its dual functions (deng2021proteinnterminalacetylation pages 2-3, ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10):

N-Terminal Region: An extended, largely disordered N-terminus containing the atypical Y-type LIR motif (Y49AEE52) for LC3/GABARAP binding. This region also harbors hydrophobic patches and low-complexity regions that contribute to HYPK self-oligomerization during stress (ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10).

Central Long α-Helix: A long α-helical region that connects the N-terminal and C-terminal domains and likely contributes to the overall structural organization of HYPK (deng2021proteinnterminalacetylation pages 2-3).

C-Terminal UBA Domain: A three-helix bundle UBA domain (~45 amino acids) homologous to the C-terminus of NACα and structurally similar to the second UBA domain of NUB1 (klein2024multiproteinassembliesorchestrate pages 2-3, ghosh2022hypkcoordinatesdegradation pages 8-10). This domain mediates interactions with NEDD8, ubiquitin-like modifiers, and the NatA complex. Key conserved residues D94, E101, L113, and G118 are critical for NEDD8 binding (ghosh2022hypkcoordinatesdegradation pages 8-10).

The domain architecture of HYPK is consistent with the UniProt annotations indicating Huntingtin-int_K, HYPK_UBA, and NAC-like_UBA domains, and is supported by crystal structures and cryo-EM reconstructions (lentzsch2024nacguidesa pages 1-9, klein2024multiproteinassembliesorchestrate pages 2-3, ghosh2022hypkcoordinatesdegradation pages 8-10).

Subcellular Localization

HYPK exhibits dynamic subcellular localization that reflects its dual roles:

Ribosome-Associated Localization: HYPK localizes to polysomes and has been reported to co-localize with ribosome-associated factors (klein2024multiproteinassembliesorchestrate pages 2-3). Cryo-EM structures from 2024 reveal HYPK in complex with NatA on the surface of translating 80S ribosomes, positioned near the polypeptide exit tunnel in coordination with NAC and methionine aminopeptidases (klein2024multiproteinassembliesorchestrate pages 1-2, lentzsch2024nacguidesa pages 1-9, klein2024multiproteinassembliesorchestrate pages 2-3). This ribosomal localization supports HYPK's role in regulating co-translational N-terminal acetylation.

Cytoplasmic Stress Granule Formation: During proteotoxic stress (e.g., induced by puromycin treatment), HYPK forms cytoplasmic foci or granules that colocalize with NEDD8-modified protein aggregates and LC3-positive autophagosomal structures (ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 4-6, ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10). This relocalization is neddylation-dependent: NEDD8 knockdown prevents HYPK granule formation (ghosh2022hypkcoordinatesdegradation pages 8-10). The granules represent sites of HYPK-mediated aggrephagy, where polyneddylated aggregates are sequestered and delivered to autophagosomes for degradation.

Biological Pathways and Processes

Co-Translational N-Terminal Acetylation Pathway

HYPK participates in the coordinated processing of nascent polypeptides emerging from the ribosome. This pathway involves sequential enzymatic steps:

N-Terminal Methionine Excision (NME): Methionine aminopeptidases (MAP1 and MAP2) cleave the initiator methionine from nascent chains when the second residue is small and uncharged (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3).
N-Terminal Acetylation (NTA): The NatA complex (NAA10-NAA15) acetylates the newly exposed N-terminus (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3, damme2021chartingthenterminal pages 1-2).

HYPK regulates this process through its interactions with NatA and coordination with NAC. Structural studies show that NatA can occupy a non-intrusive "distal" ribosomal binding site compatible with concurrent MAP1 or MAP2 binding, allowing both enzymatic activities to operate in close proximity (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3). NAC facilitates MAP1 recruitment and helps organize a dynamic multi-enzyme assembly that includes HYPK-NatA (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3). HYPK's inhibitory activity on NatA may provide temporal control, ensuring that acetylation occurs only after appropriate substrate exposure and MAP activity (deng2021proteinnterminalacetylation pages 2-3, klein2024multiproteinassembliesorchestrate pages 2-3).

Dysregulation of NatA function has been linked to congenital heart disease and neurodevelopmental disorders, highlighting the importance of HYPK as a regulatory component (ward2021mechanismsofcongenital pages 1-2).

NEDD8-Dependent Selective Autophagy (Aggrephagy) Pathway

HYPK mediates a specialized autophagy pathway for polyneddylated protein aggregates:

Proteotoxic Stress and Neddylation: Under proteotoxic conditions (e.g., translation inhibition, misfolding stress), certain misfolded proteins become modified with NEDD8 chains. This polyneddylation marks aggregation-prone substrates, including mutant huntingtin exon 1 (HTT97Q exon 1) (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 4-6).
HYPK-Mediated Recognition and Sequestration: HYPK recognizes polyneddylated aggregates via its UBA domain and self-oligomerizes to form annular structures that sequester heterogeneous protein aggregates (ghosh2022hypkcoordinatesdegradation pages 8-10). These HYPK-positive granules colocalize with NEDD8 and LC3, forming sites of autophagosomal cargo capture (ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10).
Autophagosome Formation and Maturation: HYPK's LIR-mediated interaction with LC3/GABARAP recruits autophagosomal membranes to the neddylated cargo. HYPK also promotes autophagy initiation by enhancing BECN1 phosphorylation and LC3 lipidation (ghosh2022hypkcoordinatesdegradation pages 2-4, ghosh2022hypkcoordinatesdegradation pages 10-11). Autophagosomes mature into autolysosomes for degradation of the sequestered aggregates.
Cytoprotection: This pathway protects cells from proteotoxic damage. HYPK or NEDD8 depletion impairs aggregate clearance, leading to accumulation of toxic aggregates such as mutant HTT exon 1, whereas HYPK or NEDD8 overexpression enhances clearance (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 4-6).

This NEDD8-HYPK-LC3 axis represents a noncanonical autophagy pathway distinct from the well-known ubiquitin-SQSTM1-LC3 pathway. SQSTM1 levels remain unchanged during HYPK-mediated autophagy, indicating pathway independence (ghosh2022hypkcoordinatesdegradation pages 2-4, ghosh2022hypkcoordinatesdegradation pages 8-10).

Biological Significance and Disease Relevance

Huntington's Disease and Proteostasis

HYPK was originally identified as a huntingtin-interacting protein (liu2023huntingtininteractingproteins pages 1-2, liu2023huntingtininteractingproteins pages 2-4). Its name reflects this discovery, and recent work has mechanistically connected this identity to aggregate clearance. Mutant huntingtin with expanded polyglutamine tracts forms toxic aggregates that are polyneddylated and recognized by HYPK for autophagic degradation (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 6-8). Thus, HYPK links its original huntingtin-interacting function to a defined role in Huntington's disease-relevant proteostasis (ghosh2022hypkcoordinatesdegradation pages 1-2, liu2023huntingtininteractingproteins pages 2-4).

Developmental and Neurological Disorders

The NatA complex is essential for development, and haploinsufficiency of NAA15 (the NatA auxiliary subunit with which HYPK interacts) causes congenital heart disease and neurodevelopmental deficits (ward2021mechanismsofcongenital pages 1-2). HYPK's regulatory role in NatA function suggests that perturbations in HYPK expression or activity could contribute to similar disorders. Additionally, HYPK has been implicated in regulating autophagy and protein folding responses, and its interaction with proteins involved in cell cycle arrest and unfolded protein response underscores broader roles in cellular homeostasis (pozoga2022fromnucleusto pages 1-2).

Stress Responses

HYPK functions as a proteostasis factor during stress. Its ability to form stress granules, recognize neddylated aggregates, and promote autophagy positions HYPK as a key player in the cellular response to proteotoxic insults (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 2-4, ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10). This role has implications for aging, neurodegeneration, and cancer, where protein quality control is frequently compromised.

Recent Developments (2023-2024)

Recent structural biology advances have dramatically refined our understanding of HYPK:

2024 Cryo-EM Studies: High-resolution cryo-EM structures of human NatA-ribosome complexes, including ternary assemblies with MAP2 or NAC-MAP1, have revealed the precise positioning and conformational dynamics of HYPK-associated NatA during co-translational processing (klein2024multiproteinassembliesorchestrate pages 1-2, lentzsch2024nacguidesa pages 1-9). These studies show that HYPK induces rearrangements in NAA15 that are distinct from but complementary to ribosome binding, supporting a model in which HYPK fine-tunes NatA assembly states (klein2024multiproteinassembliesorchestrate pages 2-3).

2023 Reviews on Huntingtin-Interacting Proteins: Comprehensive reviews have integrated HYPK into the broader network of huntingtin-interacting proteins, highlighting its role in both NatA regulation and autophagy as dual mechanisms by which HYPK may influence Huntington's disease pathogenesis (liu2023huntingtininteractingproteins pages 1-2, liu2023huntingtininteractingproteins pages 2-4).

2024 Studies on NAT Regulation in Plants: Comparative studies in photosynthetic organisms have shown that HYPK homologs also regulate NatA in plants, where they influence stress responses and protein stability, suggesting evolutionary conservation of HYPK's regulatory functions (pozoga2022fromnucleusto pages 1-2, giglione2021evolutiondrivenversatilityof pages 1-6).

2024 Influenza and Acetylation: HYPK was identified as part of a regulatory network involving the NatA complex that affects influenza A virus replication, underscoring roles for HYPK in host-pathogen interactions mediated through acetylation pathways (klein2024multiproteinassembliesorchestrate pages 1-2).

Summary Table of HYPK Functions

Function/Role	Molecular Mechanism	Key Domains/Motifs	Binding Partners	Subcellular Localization	Biological Processes
NatA regulatory subunit / co-translational processing factor	HYPK physically associates with the human NatA complex (NAA10-NAA15), has a strong stabilizing effect on the complex, and inhibits NAA10 catalytic activity. Structural studies indicate HYPK binding to the NAA15 helical scaffold induces conformational rearrangements that can allosterically hinder NAA50 association, helping regulate the composition and activity of ribosome-bound N-terminal acetylation machinery. HYPK is therefore a regulator, not a catalytic enzyme itself. (deng2021proteinnterminalacetylation pages 2-3, klein2024multiproteinassembliesorchestrate pages 2-3, deng2021proteinnterminalacetylation pages 3-5)	C-terminal three-helix bundle UBA domain; central long α-helix; extended/disordered N-terminus; Huntingtin-int_K/HYPK_UBA-compatible architecture from UniProt is consistent with the NatA-bound structural literature. (klein2024multiproteinassembliesorchestrate pages 2-3, deng2021proteinnterminalacetylation pages 3-5)	NAA10, NAA15, indirectly antagonizes NAA50 association with NatA; functionally linked to NAC and MAP1/MAP2 assemblies on the ribosome. (klein2024multiproteinassembliesorchestrate pages 2-3, damme2021chartingthenterminal pages 1-2)	Ribosome-associated; polysome-associated; positioned near the ribosomal polypeptide tunnel exit together with NatA and NAC during nascent-chain processing. (klein2024multiproteinassembliesorchestrate pages 2-3, lentzsch2024nacguidesa pages 1-9)	Co-translational N-terminal acetylation; coordination of N-terminal methionine excision and N-terminal acetylation; early protein biogenesis and proteostasis. (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3, damme2021chartingthenterminal pages 1-2)
Organizer of ribosome-proximal multi-enzyme assemblies	Recent cryo-EM work places NatA in a distal ribosomal site compatible with co-occupancy by MAP2 or by NAC-MAP1. HYPK-associated structural rearrangements in NAA15 resemble part of the plasticity required for ribosome engagement, supporting a model in which HYPK helps tune assembly states of the co-translational processing apparatus rather than acting as a substrate-binding enzyme. (klein2024multiproteinassembliesorchestrate pages 2-3)	Interface-forming helical architecture; flexible/disordered N-terminus likely supports dynamic assembly; C-terminal UBA domain homologous in part to NACα C-terminus per recent discussion. (klein2024multiproteinassembliesorchestrate pages 2-3)	NatA complex, NAC, MAP1/MAP2-linked ribosome processing environment. (klein2024multiproteinassembliesorchestrate pages 2-3)	80S ribosome surface at/near the polypeptide exit tunnel. (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3)	Dynamic assembly of ribosome-associated factors; coordination of sequential processing of nascent polypeptides. (klein2024multiproteinassembliesorchestrate pages 1-2, klein2024multiproteinassembliesorchestrate pages 2-3)
Selective autophagy receptor for polyneddylated cargo	HYPK acts as a scaffold that links polyneddylated aggregates to the autophagy machinery. It binds NEDD8 through its C-terminal UBA domain and binds LC3/GABARAP proteins through an N-terminal atypical LC3-interacting region, thereby promoting autophagic sequestration and degradation of neddylated protein aggregates. This defines HYPK as an autophagy receptor in NEDD8-dependent aggrephagy. (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10)	C-terminal UBA domain; N-terminal atypical tyrosine-type LIR motif Y49AEE52. (ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10)	NEDD8; LC3A; LC3B; GABARAP; GABARAPL1; GABARAPL2. (ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10)	Cytoplasmic puncta/granules; colocalizes with NEDD8 granules and LC3-positive autophagic structures during proteotoxic stress. (ghosh2022hypkcoordinatesdegradation pages 4-6, ghosh2022hypkcoordinatesdegradation pages 10-11)	Selective autophagy; aggrephagy; proteotoxic stress response; clearance of insoluble protein aggregates. (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 4-6, ghosh2022hypkcoordinatesdegradation pages 10-11)
NEDD8-binding cargo adaptor	HYPK noncovalently binds monomeric NEDD8 and polyneddylated chains. Mutational analysis identified conserved UBA residues D94, E101, L113, and G118 as important for efficient NEDD8 binding; modeling suggests E101 and G118 are exposed for direct interaction whereas D94 and L113 help stabilize the UBA fold. (ghosh2022hypkcoordinatesdegradation pages 8-10)	UBA domain; critical residues D94, E101, L113, G118. (ghosh2022hypkcoordinatesdegradation pages 8-10)	NEDD8; likely recognizes polyneddylated aggregate cargo including mutant HTT exon 1. (ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 8-10)	Cytoplasm, especially stress-induced aggregate-containing regions. (ghosh2022hypkcoordinatesdegradation pages 4-6, ghosh2022hypkcoordinatesdegradation pages 8-10)	Recognition of neddylated aggregates as autophagic cargo; noncanonical NEDD8-mediated protein quality control. (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 8-10)
LC3/GABARAP-binding autophagy scaffold	HYPK contains a noncanonical Y-type LIR in its N-terminal region. Biochemical and cell-based assays show full-length HYPK and its N-terminal fragment bind LC3B, whereas mutation of the Y49/E51/E52 region disrupts this interaction, demonstrating a direct mechanism for autophagosome recruitment. (ghosh2022hypkcoordinatesdegradation pages 10-11)	Atypical LIR motif Y49AEE52 in N-terminal region. (ghosh2022hypkcoordinatesdegradation pages 10-11)	LC3B and other ATG8-family proteins. (ghosh2022hypkcoordinatesdegradation pages 10-11)	Cytoplasmic autophagic membranes/puncta. (ghosh2022hypkcoordinatesdegradation pages 10-11)	Autophagosome formation and maturation; selective autophagy receptor function. (ghosh2022hypkcoordinatesdegradation pages 10-11)
Positive modulator of basal and stress-induced autophagy	HYPK depletion lowers LC3B-II levels and LC3 puncta, whereas overexpression increases autophagosomes and supports ongoing autophagic flux and autolysosome formation. Thus HYPK is not only a cargo receptor but also a positive regulator of autophagy efficiency in several human cell systems. (ghosh2022hypkcoordinatesdegradation pages 10-11)	UBA-LIR dual-module scaffold; self-oligomerization-promoting regions contribute to puncta formation. (ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10)	LC3 family proteins; NEDD8-modified cargo; autophagy machinery downstream of cargo recognition. (ghosh2022hypkcoordinatesdegradation pages 10-11, ghosh2022hypkcoordinatesdegradation pages 8-10)	Cytoplasm; autophagosome/autolysosome pathway. (ghosh2022hypkcoordinatesdegradation pages 10-11)	Basal autophagy; stress-induced autophagy; autophagic flux maintenance. (ghosh2022hypkcoordinatesdegradation pages 4-6, ghosh2022hypkcoordinatesdegradation pages 10-11)
Proteostasis factor linked to mutant huntingtin aggregate clearance	In cell models, NEDD8 and HYPK promote clearance of mutant HTT exon 1 aggregates by autophagy. HYPK therefore connects its original huntingtin-interacting identity with a mechanistically defined role in aggregate disposal, especially for proteotoxic, aggregation-prone substrates. (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 6-8, liu2023huntingtininteractingproteins pages 2-4)	Huntingtin-interacting protein architecture with UBA and LIR modules enabling cargo recognition and autophagy coupling. (liu2023huntingtininteractingproteins pages 2-4, ghosh2022hypkcoordinatesdegradation pages 8-10)	Mutant HTT exon 1 aggregates; NEDD8; LC3. (ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 10-11)	Cytoplasmic aggregate foci in neuronal and other cultured cells under proteotoxic stress. (ghosh2022hypkcoordinatesdegradation pages 6-8, ghosh2022hypkcoordinatesdegradation pages 10-11)	Aggregate clearance, cytoprotection during proteotoxic stress, Huntington disease-relevant protein quality control. (ghosh2022hypkcoordinatesdegradation pages 1-2, ghosh2022hypkcoordinatesdegradation pages 6-8, liu2023huntingtininteractingproteins pages 2-4)
Context within NatA biology and human disease-related proteostasis	NatA modifies up to ~40-50% of mammalian proteins, primarily iMet-processed N-termini beginning with Ser/Ala/Gly/Thr/Val/Cys; HYPK does not define substrate sequence specificity itself but regulates the major NatA complex that does. Disturbance of NatA biology is linked to developmental disease, underscoring the importance of HYPK as a regulatory component of this pathway. (damme2021chartingthenterminal pages 1-2, ward2021mechanismsofcongenital pages 1-2)	NatA-associated regulatory architecture rather than catalytic GNAT fold. (deng2021proteinnterminalacetylation pages 2-3, damme2021chartingthenterminal pages 1-2)	NAA10, NAA15, functionally NAA50-associated NatE states. (damme2021chartingthenterminal pages 1-2, ward2021mechanismsofcongenital pages 1-2)	Ribosome-associated cytosol. (damme2021chartingthenterminal pages 1-2)	N-terminal acetylome regulation, protein stability control, developmental proteostasis. (damme2021chartingthenterminal pages 1-2, ward2021mechanismsofcongenital pages 1-2)

Table: This table summarizes the best-supported molecular functions, domains, interactions, localization, and biological roles of human HYPK from the collected literature. It highlights the protein’s dual roles in NatA-mediated co-translational protein processing and NEDD8-dependent selective autophagy.

Conclusions

HYPK (Huntingtin-interacting protein K) is a multifunctional regulatory protein with two principal, mechanistically distinct roles: (1) as a non-catalytic regulatory subunit of the NatA N-terminal acetyltransferase complex, where it stabilizes the complex and allosterically inhibits catalytic activity while coordinating co-translational nascent chain processing; and (2) as a selective autophagy receptor for polyneddylated protein aggregates during proteotoxic stress, bridging NEDD8-modified cargo to LC3/GABARAP-positive autophagosomes.

HYPK localizes to ribosomes for NatA regulation and to cytoplasmic stress granules for aggrephagy. Its domain architecture—comprising an N-terminal LIR-containing disordered region, a central α-helix, and a C-terminal UBA domain—supports these dual scaffolding functions. HYPK does not possess intrinsic enzymatic activity or substrate specificity; rather, it modulates the activity of the NatA complex (which acetylates ~40-50% of the mammalian proteome) and facilitates the degradation of specific NEDD8-modified aggregates.

Recent structural studies from 2024 have provided unprecedented molecular detail on HYPK's integration into ribosomal multi-enzyme assemblies and its regulatory mechanisms. Dysregulation of HYPK-associated pathways has been implicated in developmental disorders, neurodegeneration (particularly Huntington's disease), and proteostasis defects. HYPK thus represents a critical node linking co-translational protein processing and stress-induced protein quality control, with broad implications for cellular homeostasis and disease.

References

(liu2023huntingtininteractingproteins pages 1-2): Li Liu, Huichun Tong, Yize Sun, Xingxing Chen, Tianqi Yang, Gongke Zhou, Xiao-Jiang Li, and Shihua Li. Huntingtin interacting proteins and pathological implications. International Journal of Molecular Sciences, 24:13060, Aug 2023. URL: https://doi.org/10.3390/ijms241713060, doi:10.3390/ijms241713060. This article has 23 citations.
(liu2023huntingtininteractingproteins pages 2-4): Li Liu, Huichun Tong, Yize Sun, Xingxing Chen, Tianqi Yang, Gongke Zhou, Xiao-Jiang Li, and Shihua Li. Huntingtin interacting proteins and pathological implications. International Journal of Molecular Sciences, 24:13060, Aug 2023. URL: https://doi.org/10.3390/ijms241713060, doi:10.3390/ijms241713060. This article has 23 citations.
(deng2021proteinnterminalacetylation pages 2-3): Sunbin Deng and Ronen Marmorstein. Protein n-terminal acetylation: structural basis, mechanism, versatility, and regulation. Jan 2021. URL: https://doi.org/10.1016/j.tibs.2020.08.005, doi:10.1016/j.tibs.2020.08.005. This article has 116 citations and is from a domain leading peer-reviewed journal.
(damme2021chartingthenterminal pages 1-2): Petra Van Damme. Charting the n-terminal acetylome: a comprehensive map of human nata substrates. International Journal of Molecular Sciences, 22:10692, Oct 2021. URL: https://doi.org/10.3390/ijms221910692, doi:10.3390/ijms221910692. This article has 13 citations.
(klein2024multiproteinassembliesorchestrate pages 2-3): Marius Klein, Klemens Wild, and Irmgard Sinning. Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-51964-9, doi:10.1038/s41467-024-51964-9. This article has 22 citations and is from a highest quality peer-reviewed journal.
(klein2024multiproteinassembliesorchestrate pages 1-2): Marius Klein, Klemens Wild, and Irmgard Sinning. Multi-protein assemblies orchestrate co-translational enzymatic processing on the human ribosome. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-51964-9, doi:10.1038/s41467-024-51964-9. This article has 22 citations and is from a highest quality peer-reviewed journal.
(lentzsch2024nacguidesa pages 1-9): Alfred M. Lentzsch, Denis Yudin, Martin Gamerdinger, Sowmya Chandrasekar, Laurenz Rabl, Alain Scaiola, Elke Deuerling, Nenad Ban, and Shu-ou Shan. Nac guides a ribosomal multienzyme complex for nascent protein processing. Nature, 633:718-724, Aug 2024. URL: https://doi.org/10.1038/s41586-024-07846-7, doi:10.1038/s41586-024-07846-7. This article has 36 citations and is from a highest quality peer-reviewed journal.
(ghosh2022hypkcoordinatesdegradation pages 1-2): Debasish Kumar Ghosh and Akash Ranjan. Hypk coordinates degradation of polyneddylated proteins by autophagy. Autophagy, 18:1763-1784, Nov 2022. URL: https://doi.org/10.1080/15548627.2021.1997053, doi:10.1080/15548627.2021.1997053. This article has 31 citations and is from a domain leading peer-reviewed journal.
(ghosh2022hypkcoordinatesdegradation pages 2-4): Debasish Kumar Ghosh and Akash Ranjan. Hypk coordinates degradation of polyneddylated proteins by autophagy. Autophagy, 18:1763-1784, Nov 2022. URL: https://doi.org/10.1080/15548627.2021.1997053, doi:10.1080/15548627.2021.1997053. This article has 31 citations and is from a domain leading peer-reviewed journal.
(ghosh2022hypkcoordinatesdegradation pages 6-8): Debasish Kumar Ghosh and Akash Ranjan. Hypk coordinates degradation of polyneddylated proteins by autophagy. Autophagy, 18:1763-1784, Nov 2022. URL: https://doi.org/10.1080/15548627.2021.1997053, doi:10.1080/15548627.2021.1997053. This article has 31 citations and is from a domain leading peer-reviewed journal.
(ghosh2022hypkcoordinatesdegradation pages 8-10): Debasish Kumar Ghosh and Akash Ranjan. Hypk coordinates degradation of polyneddylated proteins by autophagy. Autophagy, 18:1763-1784, Nov 2022. URL: https://doi.org/10.1080/15548627.2021.1997053, doi:10.1080/15548627.2021.1997053. This article has 31 citations and is from a domain leading peer-reviewed journal.
(ghosh2022hypkcoordinatesdegradation pages 10-11): Debasish Kumar Ghosh and Akash Ranjan. Hypk coordinates degradation of polyneddylated proteins by autophagy. Autophagy, 18:1763-1784, Nov 2022. URL: https://doi.org/10.1080/15548627.2021.1997053, doi:10.1080/15548627.2021.1997053. This article has 31 citations and is from a domain leading peer-reviewed journal.
(ghosh2022hypkcoordinatesdegradation pages 4-6): Debasish Kumar Ghosh and Akash Ranjan. Hypk coordinates degradation of polyneddylated proteins by autophagy. Autophagy, 18:1763-1784, Nov 2022. URL: https://doi.org/10.1080/15548627.2021.1997053, doi:10.1080/15548627.2021.1997053. This article has 31 citations and is from a domain leading peer-reviewed journal.
(ward2021mechanismsofcongenital pages 1-2): Tarsha Ward, Warren Tai, Sarah Morton, Francis Impens, Petra Van Damme, Delphi Van Haver, Evy Timmerman, Gabriela Venturini, Kehan Zhang, Min Young Jang, Jon A.L. Willcox, Alireza Haghighi, Bruce D. Gelb, Wendy K. Chung, Elizabeth Goldmuntz, George A. Porter, Richard P. Lifton, Martina Brueckner, H. Joseph Yost, Benoit G. Bruneau, Joshua Gorham, Yuri Kim, Alexandre Pereira, Jason Homsy, Craig C. Benson, Steven R. DePalma, Sylvia Varland, Christopher S. Chen, Thomas Arnesen, Kris Gevaert, Christine Seidman, and J.G. Seidman. Mechanisms of congenital heart disease caused by naa15 haploinsufficiency. Circulation Research, 128:1156-1169, Apr 2021. URL: https://doi.org/10.1161/circresaha.120.316966, doi:10.1161/circresaha.120.316966. This article has 47 citations and is from a highest quality peer-reviewed journal.
(pozoga2022fromnucleusto pages 1-2): Marlena Pożoga, Laura Armbruster, and Markus Wirtz. From nucleus to membrane: a subcellular map of the n-acetylation machinery in plants. International Journal of Molecular Sciences, 23:14492, Nov 2022. URL: https://doi.org/10.3390/ijms232214492, doi:10.3390/ijms232214492. This article has 13 citations.
(giglione2021evolutiondrivenversatilityof pages 1-6): Carmela Giglione and Thierry Meinnel. Evolution-driven versatility of n terminal acetylation in photoautotrophs. Apr 2021. URL: https://doi.org/10.1016/j.tplants.2020.11.012, doi:10.1016/j.tplants.2020.11.012. This article has 44 citations and is from a domain leading peer-reviewed journal.
(deng2021proteinnterminalacetylation pages 3-5): Sunbin Deng and Ronen Marmorstein. Protein n-terminal acetylation: structural basis, mechanism, versatility, and regulation. Jan 2021. URL: https://doi.org/10.1016/j.tibs.2020.08.005, doi:10.1016/j.tibs.2020.08.005. This article has 116 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

klein2024multiproteinassembliesorchestrate pages 2-3
damme2021chartingthenterminal pages 1-2
ghosh2022hypkcoordinatesdegradation pages 8-10
ghosh2022hypkcoordinatesdegradation pages 10-11
ghosh2022hypkcoordinatesdegradation pages 2-4
deng2021proteinnterminalacetylation pages 2-3
ward2021mechanismsofcongenital pages 1-2
pozoga2022fromnucleusto pages 1-2
klein2024multiproteinassembliesorchestrate pages 1-2
liu2023huntingtininteractingproteins pages 1-2
liu2023huntingtininteractingproteins pages 2-4
lentzsch2024nacguidesa pages 1-9
ghosh2022hypkcoordinatesdegradation pages 1-2
ghosh2022hypkcoordinatesdegradation pages 6-8
ghosh2022hypkcoordinatesdegradation pages 4-6
giglione2021evolutiondrivenversatilityof pages 1-6
deng2021proteinnterminalacetylation pages 3-5
https://doi.org/10.3390/ijms241713060,
https://doi.org/10.1016/j.tibs.2020.08.005,
https://doi.org/10.3390/ijms221910692,
https://doi.org/10.1038/s41467-024-51964-9,
https://doi.org/10.1038/s41586-024-07846-7,
https://doi.org/10.1080/15548627.2021.1997053,
https://doi.org/10.1161/circresaha.120.316966,
https://doi.org/10.3390/ijms232214492,
https://doi.org/10.1016/j.tplants.2020.11.012,

📚 Additional Documentation

Notes

(HYPK-notes.md)

HYPK (Q9NX55) research notes

Summary

HYPK (Huntingtin-interacting protein K) is a small, largely intrinsically disordered protein that functions as a ribosome-associated, NatA-associated chaperone. It is a stable component of the N-terminal acetyltransferase A (NatA)/HYPK complex (with the catalytic NAA10 and auxiliary NAA15 subunits), where it binds principally to NAA15 and acts as a negative regulator that reduces the N-terminal acetyltransferase activity of NatA and modulates its interaction with NAA50 (the NatE catalytic subunit). Independently of catalysis, HYPK has chaperone-like activity: it suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine (polyQ) aggregation of an expanded N-terminal huntingtin (HTT) fragment in neuronal cells, an activity it exerts in association with the NatA complex. Through these chaperone and complex-modulating roles HYPK contributes to protein stabilization and is reported to negatively regulate apoptosis. HYPK is found in both the cytoplasm and the nucleus.

Core functions (from review)

GO:0044183 protein folding chaperone — Intrinsically disordered, ribosome/NatA-associated chaperone that suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine aggregation of N-terminal huntingtin, acting in association with the NatA complex.
GO:0010699 acetyltransferase inhibitor activity — Non-catalytic regulatory subunit of the NatA/HYPK N-terminal acetyltransferase complex that binds NAA15 and reduces (inhibits) the N-terminal acetyltransferase activity of the NAA10-NAA15 (NatA) complex and modulates its interaction with NAA50.

Provenance

Research and verbatim supporting quotes are recorded inline in HYPK-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(HYPK-pn-notes.md)

HYPK PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9NX55
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07c
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/HYPK/HYPK-ai-review.yaml
AIGR review HTML: present - genes/human/HYPK/HYPK-ai-review.html
Gene notes: present - genes/human/HYPK/HYPK-notes.md
GOA TSV: present - genes/human/HYPK/HYPK-goa.tsv
UniProt record: present - genes/human/HYPK/HYPK-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/HYPK.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/HYPK.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: HYPK (Huntingtin-interacting protein K) is a small, largely intrinsically disordered protein that functions as a ribosome-associated, NatA-associated chaperone. It is a stable component of the N-terminal acetyltransferase A (NatA)/HYPK complex (with the catalytic NAA10 and auxiliary NAA15 subunits), where it binds principally to NAA15 and acts as a negative regulator that reduces the N-terminal acetyltransferase activity of NatA and modulates its interaction with NAA50 (the NatE catalytic subunit). Independently of catalysis, HYPK has chaperone-like activity: it suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine (polyQ) aggregation of an expanded N-terminal huntingtin (HTT) fragment in neuronal cells, an activity it exerts in association with the NatA complex. Through these chaperone and complex-modulating roles HYPK contributes to protein stabilization and is reported to negatively regulate apoptosis. HYPK is found in both the cytoplasm and the nucleus.
Existing/core annotation action counts: ACCEPT: 5; KEEP_AS_NON_CORE: 19

PN Consistency Summary

Consistency: Mostly consistent, with one tension. Deep research and review agree HYPK is an intrinsically disordered NatA-associated chaperone that (a) suppresses polyQ-HTT aggregation (GO:0044183 protein folding chaperone, EXP/IDA) and (b) is a non-catalytic NatA subunit that INHIBITS NatA N-terminal acetyltransferase activity (core_function GO:0010699 acetyltransferase inhibitor activity). The PN row-1 projection of GO:0006474 (N-terminal acetylation, the catalytic process) sits awkwardly: HYPK does not itself acetylate and the review explicitly frames HYPK as a NatA inhibitor/modulator. So PN's "performs N-terminal acetylation" projection partially contradicts the review's "inhibits/modulates NatA" reading.
PN story / NEW pressure: PN row 1 → GO:0006474 N-terminal protein amino acid acetylation (verified real). This is NOT in HYPK's GOA, but HYPK is a regulatory/modulator subunit, not a catalytic acetyltransferase — projecting the catalytic process term over-attributes activity. The review's own GO:0010699 acetyltransferase inhibitor activity (MF) and complex membership (GO:0031415 NatA complex) better capture the role. Row 2 (UPS / NACA-domain reader) is correctly no_mapping. Conclusion: over-reaches — GO:0006474 should not be propagated to HYPK as an enabling/involved_in catalytic term.
Evidence alignment: PN row 1 lists no titles; row 2 lists signature domain IPR044034 (UBA/NAC domain), no PMIDs. Review anchors on PMID:17947297 (chaperone/anti-apoptosis), PMID:18076027 (intrinsically disordered chaperone), PMID:20154145 (HYPK-NatA complex, cotranslational NAT + anti-HTT-aggregation). No citation conflict.
Verdict: Mostly consistent; PN's catalytic N-terminal-acetylation projection over-reaches for a NatA-modulator. Recommended edits: treat node GO:0006474 as context-only for HYPK (do not propagate the catalytic process term); keep the review's GO:0010699 inhibitor activity + GO:0031415 NatA complex as the accurate captures [MAP].

Full Consistency Review

UniProt: Q9NX55 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
PN placement: TWO rows. Row 1 (TR) Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide|Modulator of NatA and NatE complexes (type N-terminal acetylation=mapped→GO:0006474 N-terminal protein amino acid acetylation [new_to_goa]; subtype/group=no_mapping; class/branch=context_only). Row 2 (UPS) Ubiquitin and UBL binding|other protein modifiers|N-terminal acetylation|UBA (NACA) — all no_mapping; class=context_only→GO:0140036 ubiquitin-modified protein reader activity.
Consistency: Mostly consistent, with one tension. Deep research and review agree HYPK is an intrinsically disordered NatA-associated chaperone that (a) suppresses polyQ-HTT aggregation (GO:0044183 protein folding chaperone, EXP/IDA) and (b) is a non-catalytic NatA subunit that INHIBITS NatA N-terminal acetyltransferase activity (core_function GO:0010699 acetyltransferase inhibitor activity). The PN row-1 projection of GO:0006474 (N-terminal acetylation, the catalytic process) sits awkwardly: HYPK does not itself acetylate and the review explicitly frames HYPK as a NatA inhibitor/modulator. So PN's "performs N-terminal acetylation" projection partially contradicts the review's "inhibits/modulates NatA" reading.
PN story / NEW pressure: PN row 1 → GO:0006474 N-terminal protein amino acid acetylation (verified real). This is NOT in HYPK's GOA, but HYPK is a regulatory/modulator subunit, not a catalytic acetyltransferase — projecting the catalytic process term over-attributes activity. The review's own GO:0010699 acetyltransferase inhibitor activity (MF) and complex membership (GO:0031415 NatA complex) better capture the role. Row 2 (UPS / NACA-domain reader) is correctly no_mapping. Conclusion: over-reaches — GO:0006474 should not be propagated to HYPK as an enabling/involved_in catalytic term.
Mapping strategy: Recommend the type-node GO:0006474 be treated as context_only for HYPK (it is a regulator, not a catalyst). The review correctly does not annotate HYPK with N-terminal acetyltransferase activity. UPS-branch no_mappings are appropriate (NatA/UBA-domain reader context, no single safe GO assertion).
Evidence alignment: PN row 1 lists no titles; row 2 lists signature domain IPR044034 (UBA/NAC domain), no PMIDs. Review anchors on PMID:17947297 (chaperone/anti-apoptosis), PMID:18076027 (intrinsically disordered chaperone), PMID:20154145 (HYPK-NatA complex, cotranslational NAT + anti-HTT-aggregation). No citation conflict.
Verdict: Mostly consistent; PN's catalytic N-terminal-acetylation projection over-reaches for a NatA-modulator. Recommended edits: treat node GO:0006474 as context-only for HYPK (do not propagate the catalytic process term); keep the review's GO:0010699 inhibitor activity + GO:0031415 NatA complex as the accurate captures [MAP].

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07c
review_yaml: genes/human/HYPK/HYPK-ai-review.yaml
PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Nascent peptide husbandry | N-terminal acetylation of nascent peptide | Modulator of NatA and NatE complexes

UniProt: Q9NX55
In branches: TR, UPS
PN-node mapping records (path + ancestors):
- [subtype] Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide|Modulator of NatA and NatE complexes
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower taxonomy bucket already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
- [type] Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006474 N-terminal protein amino acid acetylation]
  rationale: This PN type denotes N-terminal acetyltransferase machinery acting on nascent peptides. The GO N-terminal acetylation process is the direct target.
- [group] Translation|Cytosolic translation|Nascent peptide husbandry
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [class] Translation|Cytosolic translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
  rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | other protein modifiers | N-terminal acetylation | UBA (NACA)

UniProt: Q9NX55
In branches: TR, UPS
Signature domains: IPR044034
Auxiliary domains: (none)
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|other protein modifiers|N-terminal acetylation|UBA (NACA)
  status=no_mapping scope= GO=[]
  rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|other protein modifiers|N-terminal acetylation
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|other protein modifiers
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0006474 N-terminal protein amino acid acetylation | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q9NX55
gene_symbol: HYPK
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HYPK (Huntingtin-interacting protein K) is a small, largely intrinsically
  disordered protein that functions as a ribosome-associated, NatA-associated
  chaperone. It is a stable component of the N-terminal acetyltransferase A
  (NatA)/HYPK complex (with the catalytic NAA10 and auxiliary NAA15 subunits),
  where it binds principally to NAA15 and acts as a negative regulator that
  reduces the N-terminal acetyltransferase activity of NatA and modulates its
  interaction with NAA50 (the NatE catalytic subunit). Independently of
  catalysis, HYPK has chaperone-like activity: it suppresses aggregation of
  aggregation-prone clients, notably preventing polyglutamine (polyQ)
  aggregation of an expanded N-terminal huntingtin (HTT) fragment in neuronal
  cells, an activity it exerts in association with the NatA complex. Through
  these chaperone and complex-modulating roles HYPK contributes to protein
  stabilization and is reported to negatively regulate apoptosis. HYPK is found
  in both the cytoplasm and the nucleus.
alternative_products:
- name: '2'
  id: Q9NX55-2
- name: '3'
  id: Q9NX55-3
  sequence_note: VSP_040677, VSP_040678
existing_annotations:
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that HYPK negatively regulates apoptosis, a process downstream of its chaperone/anti-aggregation activity.
    action: KEEP_AS_NON_CORE
    reason: Documented experimentally and by family inference but a downstream consequence of HYPK's chaperone role rather than its core molecular function.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0043066 negative regulation of apoptotic process biological_process IDA PMID:17947297
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that HYPK stabilizes proteins, consistent with its anti-aggregation chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: A plausible biological-process outcome of HYPK's chaperone function; retained as non-core relative to the chaperone MF.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0050821 protein stabilization biological_process IDA PMID:17947297
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of nuclear localization, consistent with the documented nuclear pool of HYPK.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool documented; HYPK's core NatA-associated/chaperone role is cytoplasmic/ribosome-associated, so nuclear localization is non-core.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:20154145
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of cytoplasmic localization, the principal site of HYPK's NatA-associated and chaperone activity.
    action: ACCEPT
    reason: Cytoplasm is the main site of HYPK function; well supported.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component EXP PMID:20154145
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inferred from the protein-folding-chaperone MF; HYPK participates in protein folding/quality control as a chaperone.
    action: KEEP_AS_NON_CORE
    reason: A reasonable process annotation downstream of HYPK's chaperone MF; kept non-core.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-uniprot.txt
      supporting_text: Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17500595
  qualifier: enables
  review:
    summary: IntAct interaction with HTT (P42858, huntingtin), the namesake client of HYPK. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important HYPK-HTT interaction; informative function (chaperone) captured elsewhere.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:17500595 UniProtKB:P42858
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  qualifier: enables
  review:
    summary: IntAct interaction with NAA15 (Q9BXJ9), HYPK's principal NatA-complex partner. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the central HYPK-NAA15 interaction underlying NatA/HYPK complex formation; informative function captured elsewhere.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:24981860 UniProtKB:Q9BXJ9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale yeast two-hybrid interactome (e.g. P40222, P43355). Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; uninformative as a core MF.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:25416956 UniProtKB:P40222
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interaction with NAA15 (Q9BXJ9). Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the central HYPK-NAA15 interaction; informative function captured elsewhere.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:28514442 UniProtKB:Q9BXJ9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput interactome capturing NAA15 (Q9BXJ9) and other partners. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions including HYPK-NAA15; generic MF kept non-core.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:32296183 UniProtKB:Q9BXJ9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome capturing the HYPK-HTT (P42858) interaction. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the HYPK-HTT interaction; informative function captured elsewhere.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:32814053 UniProtKB:P42858
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex interactome capturing NAA15 (Q9BXJ9). Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the HYPK-NAA15 interaction; generic MF kept non-core.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:33961781 UniProtKB:Q9BXJ9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome capturing NAA15 (Q9BXJ9). Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the HYPK-NAA15 interaction; generic MF kept non-core.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:40205054 UniProtKB:Q9BXJ9
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence nucleoplasmic localization, consistent with the documented nuclear pool of HYPK.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool documented; non-core relative to cytoplasmic NatA-associated function.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component IDA GO_REF:0000052 HPA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:20154145
  qualifier: located_in
  review:
    summary: Experimental nuclear localization of HYPK.
    action: KEEP_AS_NON_CORE
    reason: Documented nuclear pool; non-core relative to cytoplasmic function.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:20154145
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:20154145
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic localization, the principal site of HYPK function.
    action: ACCEPT
    reason: Core localization for HYPK's NatA-associated and chaperone roles.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component EXP PMID:20154145
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: EXP
  original_reference_id: PMID:18076027
  qualifier: enables
  review:
    summary: Experimental evidence (DisProt) that the intrinsically disordered HYPK acts as a chaperone preventing aggregation of clients; the core molecular function.
    action: ACCEPT
    reason: Direct experimental evidence for HYPK's chaperone activity; this is its core, informative non-catalytic MF.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-uniprot.txt
      supporting_text: Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:18076027
  qualifier: enables
  review:
    summary: Direct experimental evidence for HYPK chaperone activity; core MF.
    action: ACCEPT
    reason: Direct experimental support for the core chaperone function.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-uniprot.txt
      supporting_text: Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17947297
  qualifier: enables
  review:
    summary: IntAct interaction with HTT (P42858); the original HYPK-huntingtin interaction underpinning its anti-polyQ-aggregation activity. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central HYPK-HTT interaction; informative chaperone function captured elsewhere.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:17947297 UniProtKB:P42858
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17947297
  qualifier: located_in
  review:
    summary: Direct nuclear localization of HYPK.
    action: KEEP_AS_NON_CORE
    reason: Documented nuclear pool; non-core relative to cytoplasmic function.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component IDA PMID:17947297
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17947297
  qualifier: located_in
  review:
    summary: Direct cytoplasmic localization of HYPK.
    action: ACCEPT
    reason: Core localization for HYPK function.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component IDA PMID:17947297
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:17947297
  qualifier: part_of
  review:
    summary: HYPK is part of a protein complex; this is captured more precisely by its membership in the NatA/HYPK complex.
    action: KEEP_AS_NON_CORE
    reason: Generic complex term; HYPK's specific complex is the NatA/HYPK complex, so this high-level CC term is retained non-core. Recent cryo-EM-based synthesis places this HYPK-NatA assembly on translating ribosomes near the polypeptide exit tunnel together with NAC and the methionine aminopeptidases.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-uniprot.txt
      supporting_text: Component of the N-terminal acetyltransferase A (NatA)/HYPK complex at least composed of NAA10, NAA15 and HYPK
    - reference_id: file:human/HYPK/HYPK-deep-research-falcon.md
      supporting_text: HYPK can be detected in ribosomal complexes that include NatA, the nascent polypeptide-associated complex (NAC), and methionine aminopeptidases (MAP1 or MAP2)
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:17947297
  qualifier: involved_in
  review:
    summary: Direct evidence that HYPK negatively regulates apoptosis, downstream of its anti-aggregation chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: A documented downstream process; non-core relative to the chaperone MF.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0043066 negative regulation of apoptotic process biological_process IDA PMID:17947297
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:17947297
  qualifier: involved_in
  review:
    summary: Direct evidence that HYPK stabilizes proteins (suppressing aggregation), a process outcome of its chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: Documented downstream process; non-core relative to the chaperone MF.
    supported_by:
    - reference_id: file:human/HYPK/HYPK-goa.tsv
      supporting_text: GO:0050821 protein stabilization biological_process IDA PMID:17947297
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Gene Ontology annotation based on inference from GO term-to-term logical definitions
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17500595
  title: 'Huntingtin interacting proteins are genetic modifiers of neurodegeneration.'
  findings: []
- id: PMID:17947297
  title: 'HYPK, a Huntingtin interacting protein, reduces aggregates and apoptosis induced by N-terminal Huntingtin with 40 glutamines in Neuro2a cells and exhibits chaperone-like activity.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_17947297.md title matches; richly anchored in GOA as the IDA source for GO:0050821 (protein stabilization), GO:0043066 (negative regulation of apoptotic process), GO:0032991 (protein-containing complex) and the cytoplasm/nucleus localizations. Establishes the HYPK chaperone-like anti-polyQ-aggregation core function."
  findings:
  - statement: HYPK interacts with N-terminal huntingtin, exhibits chaperone-like activity reducing polyQ aggregates and apoptosis, and localizes to cytoplasm and nucleus.
    reference_section_type: RESULTS
- id: PMID:18076027
  title: 'Huntingtin interacting protein HYPK is intrinsically unstructured.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Not cached, but anchored to GOA: this PMID is the EXP/IDA source for GO:0044183 (protein folding chaperone) for HYPK, consistent with the title. Directly supports the intrinsically-disordered-chaperone core function."
  findings:
  - statement: HYPK is intrinsically unstructured and possesses chaperone-like anti-aggregation activity.
    reference_section_type: RESULTS
- id: PMID:20154145
  title: 'The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Not cached, but anchored to GOA: this PMID is the EXP source for the cytoplasm (GO:0005737) and nucleus (GO:0005634) localizations of HYPK, consistent with the title. Establishes the HYPK-NatA (NAA10/NAA15) complex that underpins the acetyltransferase-modulating core function."
  findings:
  - statement: HYPK is a stable component of the NatA complex (with NAA10 and NAA15), and the NatA complex is required for HYPK stability and for reducing polyQ aggregation of HTT.
    reference_section_type: RESULTS
- id: PMID:24981860
  title: 'Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.'
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: "Large AP-MS interactome (Marcon et al.) that is the GOA IPI source for an HYPK interaction; relevant only as a network/interaction record, not a functional characterization. Title corrected to verbatim PubMed (the prior title was a fabricated description)."
  findings:
  - statement: HYPK interacts with NAA15 within the NatA/HYPK complex.
    reference_section_type: RESULTS
- id: PMID:25416956
  title: 'A proteome-scale map of the human interactome network.'
  findings: []
- id: PMID:28514442
  title: 'Architecture of the human interactome defines protein communities and disease networks.'
  findings: []
- id: PMID:32296183
  title: 'A reference map of the human binary protein interactome.'
  findings: []
- id: PMID:32814053
  title: 'Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.'
  findings: []
- id: PMID:33961781
  title: 'Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.'
  findings: []
- id: PMID:40205054
  title: 'Multimodal cell maps as a foundation for structural and functional genomics.'
  findings: []
- id: file:human/HYPK/HYPK-deep-research-falcon.md
  title: Falcon deep research report for HYPK
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: >-
      LLM-synthesized (Edison/Falcon) report; not independently verified, so marked UNVERIFIED.
      HYPK-specific, well-anchored claims it surfaces: (i) HYPK is a non-catalytic regulator of
      the human NatA (NAA10-NAA15) complex that stabilizes the complex and allosterically inhibits
      NAA10 (citing Klein et al. 2024 Nat Commun and Deng & Marmorstein 2021); (ii) HYPK is
      ribosome/polysome-associated near the exit tunnel together with NatA, NAC and MAP1/MAP2
      (Klein 2024; Lentzsch 2024); and (iii) a distinct, HYPK-specific role as a selective
      autophagy receptor for polyneddylated cargo via a C-terminal UBA domain (NEDD8 binding)
      and an atypical N-terminal LIR (Y49AEE52, LC3/GABARAP binding), citing the HYPK-specific
      primary paper Ghosh & Ranjan 2022 Autophagy (PMID:34320889). CAUTION: the report at points
      over-generalizes NAC-complex and general co-translational-processing functions onto HYPK,
      and over-reads the huntingtin connection (HYPK was named for HTT interaction; the polyQ
      anti-aggregation/NEDD8-aggrephagy links are HYPK-specific but the broader Huntington's
      disease relevance is inferential). The autophagy-receptor and NatA-allosteric-inhibition
      mechanisms are not yet captured by GOA annotations and are flagged for expert follow-up
      rather than used to add or remove annotations here.
  findings:
  - statement: HYPK is a non-catalytic regulator of the NatA (NAA10-NAA15) complex that stabilizes the complex and allosterically inhibits NAA10; it is ribosome/polysome-associated near the exit tunnel together with NatA, NAC and MAP1/MAP2.
    reference_section_type: RESULTS
  - statement: HYPK additionally functions as a selective autophagy receptor that bridges polyneddylated protein cargo (via its C-terminal UBA domain binding NEDD8) to LC3/GABARAP autophagosomal proteins (via an atypical N-terminal LIR), per Ghosh & Ranjan 2022.
    reference_section_type: RESULTS
core_functions:
- description: Intrinsically disordered, ribosome/NatA-associated chaperone that suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine aggregation of N-terminal huntingtin, acting in association with the NatA complex.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/HYPK/HYPK-uniprot.txt
    supporting_text: Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells
- description: Non-catalytic regulatory subunit of the NatA/HYPK N-terminal acetyltransferase complex that binds NAA15 and reduces (inhibits) the N-terminal acetyltransferase activity of the NAA10-NAA15 (NatA) complex and modulates its interaction with NAA50.
  molecular_function:
    id: GO:0004857
    label: enzyme inhibitor activity
  in_complex:
    id: GO:0031415
    label: NatA complex
  supported_by:
  - reference_id: file:human/HYPK/HYPK-uniprot.txt
    supporting_text: Inhibits the N-terminal acetylation activity of the N-terminal acetyltransferase NAA10-NAA15 complex (also called the NatA complex)
  - reference_id: file:human/HYPK/HYPK-deep-research-falcon.md
    supporting_text: HYPK inhibits the catalytic activity of NAA10 through an allosteric mechanism.
  - reference_id: file:human/HYPK/HYPK-deep-research-falcon.md
    supporting_text: HYPK binding has a strong stabilizing effect on the NatA complex
proposed_new_terms: []
suggested_questions:
- question: Is HYPK's NatA-inhibitory activity a regulatory mechanism for global N-terminal acetylation, or primarily a means to couple NatA to nascent-chain chaperoning?
- question: Does HYPK's anti-polyQ-aggregation chaperone activity require its association with the NatA complex, or can free HYPK chaperone clients independently?
- question: Should HYPK be annotated as a selective autophagy receptor for polyneddylated cargo (NEDD8-binding UBA domain plus an atypical N-terminal LIR engaging LC3/GABARAP), as reported by Ghosh & Ranjan 2022 (PMID:34320889)? This HYPK-specific aggrephagy role is not yet reflected in the current GOA annotations and warrants expert curation of the primary full text.
suggested_experiments:
- description: In vitro reconstitution measuring NatA N-terminal acetyltransferase activity with and without HYPK and NAA50 to quantify HYPK's inhibitory effect and its competition with NAA50.
- description: Aggregation assays (FRAP, filter-trap) of expanded-polyQ HTT in cells with HYPK knockout versus HYPK reconstituted in NatA-binding-deficient form to test whether chaperone activity requires NatA association.
- description: Selective ribosome profiling / N-terminal acetylome comparison upon HYPK depletion to define which nascent-chain substrates are co-regulated by HYPK and NatA.

HYPK

Gene Description

Existing Annotations Review

Core Functions

Intrinsically disordered, ribosome/NatA-associated chaperone that suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine aggregation of N-terminal huntingtin, acting in association with the NatA complex.

Non-catalytic regulatory subunit of the NatA/HYPK N-terminal acetyltransferase complex that binds NAA15 and reduces (inhibits) the N-terminal acetyltransferase activity of the NAA10-NAA15 (NatA) complex and modulates its interaction with NAA50.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: HYPK (Huntingtin-Interacting Protein K)

Gene and Protein Identity

Primary Molecular Functions

1. Regulatory Component of the NatA N-Terminal Acetyltransferase Complex

2. Selective Autophagy Receptor for Polyneddylated Protein Aggregates

Protein Structure and Domains

Subcellular Localization

Biological Pathways and Processes

Co-Translational N-Terminal Acetylation Pathway

NEDD8-Dependent Selective Autophagy (Aggrephagy) Pathway

Biological Significance and Disease Relevance

Huntington's Disease and Proteostasis

Developmental and Neurological Disorders

Stress Responses

Recent Developments (2023-2024)

Summary Table of HYPK Functions

Conclusions

Artifacts

Citations

📚 Additional Documentation

Notes

HYPK (Q9NX55) research notes

Summary

Core functions (from review)

Provenance

Pn Notes

HYPK PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Translation | Cytosolic translation | Nascent peptide husbandry | N-terminal acetylation of nascent peptide | Modulator of NatA and NatE complexes

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | other protein modifiers | N-terminal acetylation | UBA (NACA)

Projected GO annotations (1)

Note

📄 View Raw YAML