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.