{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHECTD3 is an E3 ubiquitin ligase that plays a pivotal role in innate immune signaling by mediating lysine-63 linked polyubiquitination of TRAF3 at a specific lysine residue (K138). This post-translational modification is essential for recruiting the downstream activator TBK1 and forming the TRAF3–TBK1 complex, thereby facilitating type I interferon production in response to intracellular bacterial infections. Notably, mice deficient in HECTD3 exhibit an impaired type I IFN response and altered pathogen dissemination, highlighting its critical function in modulating host defenses against bacteria."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cardiac physiology, HECTD3 exerts cardioprotective effects by simultaneously attenuating pathological cardiomyocyte hypertrophy and dampening inflammatory responses. By modulating the levels of SUMO2 and Stat1, HECTD3 interferes with both the calcineurin-NFAT hypertrophic signaling and the pro-inflammatory actions triggered by bacterial lipopolysaccharide or interferon-γ. In vivo overexpression of HECTD3 significantly reduced cardiac hypertrophy, macrophage infiltration, and fibrotic remodeling under stress conditions, thereby underscoring its therapeutic potential in mitigating heart failure-associated inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in immune and cardiac regulation, HECTD3 is also involved in the ubiquitination of proteins associated with membrane trafficking. It directly interacts with Syntaxin 8, a component involved in vesicular transport, promoting its ubiquitination and potentially influencing its turnover or function. This interaction, identified through yeast two-hybrid screening and confirmed by co-immunoprecipitation and immunofluorescence studies, suggests that HECTD3 may have broader regulatory roles extending into the control of protein sorting and intracellular membrane dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fubing Li, Yang Li, Huichun Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI120406"}], "href": "https://doi.org/10.1172/JCI120406"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29920190"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29920190"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ashraf Yusuf Rangrez, Ankush Borlepawar, Nesrin Schmiedel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Commun Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42003-020-01289-2"}], "href": "https://doi.org/10.1038/s42003-020-01289-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33037313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33037313"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lisheng Zhang, Liang Kang, William Bond, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction between syntaxin 8 and HECTd3, a HECT domain ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Neurobiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10571-008-9303-0"}], "href": "https://doi.org/10.1007/s10571-008-9303-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18821010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18821010"}]}]}]}