{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHDAC6 acts as a key regulator of cellular protein quality control by deacetylating non‐histone targets such as Hsp90. This activity modulates the chaperone’s binding to client proteins and affects the structural maturation and stability of signaling molecules, while also promoting the clearance of misfolded proteins via aggresome formation and stress granule assembly. In addition, HDAC6 recognizes and binds unanchored ubiquitin chains on protein aggregates—a function dependent on its unique ubiquitin‐binding PAZ domain—to facilitate their transport along microtubules for degradation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBy deacetylating principal components of the cytoskeleton—including α‐tubulin and the actin‐binding protein cortactin—HDAC6 exerts powerful control over microtubule dynamics, focal adhesion turnover, and cell migration. Its activity is modulated by extracellular signals (for instance, estrogen and growth factors) that enhance its cytoskeletal deacetylase function, thereby promoting changes in cell shape, enhancing motility, and regulating the assembly/disassembly of cellular adhesions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, HDAC6 has emerged as a modulator of neurodegenerative processes. It interacts directly with tau and other aggregation‐prone proteins such as TDP-43, thereby influencing tau phosphorylation and aggregation, axonal transport, and stress responses. Dysregulation of HDAC6 activity has been associated with increased tau pathology as well as impaired degradation of toxic protein species, underscoring its potential as a therapeutic target in diseases like Alzheimer’s and amyotrophic lateral sclerosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHDAC6 also contributes significantly to oncogenic processes by modulating a range of signaling pathways. Its deacetylation of targets such as β‐catenin, KRAS, and factors involved in the epithelial–mesenchymal transition (EMT) enhances tumor cell transformation, survival, and metastasis. Moreover, HDAC6 influences key cell cycle regulators and even DNA repair effectors like MSH2, with its activity correlating with enhanced anchorage‐independent growth and resistance to stress in tumor models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional regulatory aspects of HDAC6 include its participation in non‐canonical nuclear signaling and trafficking. Interactions with protein phosphatases (for example, PP1) and unique structural domains—such as a tetradecapeptide repeat region—modulate both its catalytic activity and subcellular localization, thereby influencing endosomal trafficking processes like EGFR transport and broader aspects of signal transduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHDAC6 plays a pivotal role in epithelial biology by regulating ciliary dynamics and autophagy. 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