{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HECW1, also known as NEDL1, is a HECT‐domain E3 ubiquitin ligase that exerts diverse, context‐dependent regulatory functions through targeted protein ubiquitination and degradation. In neural contexts, HECW1/NEDL1 binds mutant forms of superoxide dismutase‐1 and interacts with signaling proteins such as Dishevelled‐1 and p53 to promote ubiquitin‐mediated proteasomal degradation, thereby enhancing pro‐apoptotic activity and implicating its role in familial amyotrophic lateral sclerosis (ALS) pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n In breast cancer cells, HECW1 collaborates with related ubiquitin ligases to negatively regulate ErbB4 expression through ubiquitination‐dependent degradation, suggesting an antithetical modulation of receptor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n Furthermore, HECW1 targets the thyroid transcription factor TTF1 in both thyroid and lung epithelial cells by ubiquitinating a key lysine residue, resulting in its proteasomal degradation; this modulation of TTF1 levels influences cell migration, proliferation, and epithelial remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n In non‐small cell lung cancer, upregulated HECW1 enhances cellular proliferation, migration, and invasiveness by promoting the ubiquitination and degradation of Smad4, thereby modulating tumorigenic signaling pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n In reproductive tissues, estrogen‐stimulated HECW1 expression mediates the ubiquitination and degradation of the polarity protein Scribble, a process linked to the development of adenomyosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n Moreover, reduced HECW1 expression in patients with IgA nephropathy is correlated with higher levels of galactose‐deficient IgA1, suggesting a novel role for HECW1 in the regulation of IgA1 glycosylation and immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n Finally, recruitment of HECW1 as part of the NEDD4 family during paramyxovirus budding further implicates this ligase in host–virus interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n Collectively, these findings highlight HECW1’s multifaceted role in protein quality control and signal modulation across diverse cellular systems and disease processes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kou Miyazaki, Tomoyuki Fujita, Toshinori Ozaki, et al. 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