{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HYPK is an intrinsically unstructured, multifunctional protein that plays critical roles in maintaining cellular proteostasis. It acts as a chaperone‐like protein that assists in the folding of nascent polypeptides and, importantly, counteracts the aggregation of aberrant proteins such as mutant Huntingtin, thereby reducing aggregation‐induced cytotoxicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its classic chaperone functions, HYPK is an integral component of the ribosome‐associated N‐terminal acetyltransferase (NAT) machinery. It interacts with complexes such as NatA and NatE to modulate co‐translational N‐terminal acetylation, thereby influencing the stability, folding, and proper targeting of a large subset of proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, specific regions within HYPK, particularly its C‑terminal domain, are essential for both its chaperone‐like activity and its regulatory influence over NAT functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n HYPK is also tightly linked to cellular stress responses. It is transcriptionally regulated by heat shock factor 1 (HSF1) and is upregulated under conditions of heat shock and other cellular stresses. This regulation not only helps sustain its own expression but also contributes indirectly to the mitigation of proteotoxic stress by modulating both the heat shock response and apoptotic pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, emerging evidence indicates that HYPK can function as an autophagy receptor. By recognising and binding misfolded or aggregation‐prone proteins through defined interaction motifs, HYPK facilitates the clearance of toxic protein aggregates via autophagic pathways, thereby further safeguarding cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, the versatile activities of HYPK—including its chaperone‐like prevention of aberrant protein aggregation, its modulation of N‐terminal acetylation as part of NAT complexes, and its involvement in stress response and autophagy—underscore its importance as a global regulator of protein quality control and cellular survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Thomas Arnesen, Kristian K Starheim, Petra Van Damme, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01199-09"}], "href": "https://doi.org/10.1128/MCB.01199-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20154145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20154145"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Swasti Raychaudhuri, Mithun Sinha, Debashis Mukhopadhyay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "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."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm301"}], "href": "https://doi.org/10.1093/hmg/ddm301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17947297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17947297"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kamalika Roy Choudhury, Nitai P Bhattacharyya "}, {"type": "b", "children": [{"type": "t", "text": "Chaperone protein HYPK interacts with the first 17 amino acid region of Huntingtin and modulates mutant HTT-mediated aggregation and cytotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2014.11.035"}], "href": "https://doi.org/10.1016/j.bbrc.2014.11.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25446099"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25446099"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ewa Szolajska, Jadwiga Chroboczek "}, {"type": "b", "children": [{"type": "t", "text": "Faithful chaperones."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-011-0740-4"}], "href": "https://doi.org/10.1007/s00018-011-0740-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21655914"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21655914"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Felix Alexander Weyer, Andrea Gumiero, Karine Lapouge, et al. 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