{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRNF146, also known as Iduna, is a RING‐type E3 ubiquitin ligase whose activity is uniquely regulated by its interaction with poly(ADP‐ribose) (PAR). Structural and biochemical studies have revealed that RNF146 contains a WWE domain that binds iso-ADP-ribose—the smallest internal unit of PAR—which triggers a conformational rearrangement of its RING domain. This allosteric shift switches RNF146 from an inactive to an active state, enabling efficient recruitment of ubiquitin‐conjugating enzymes and promoting the ubiquitination of PARylated substrates."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRNF146 also plays a pivotal role in modulating key signaling pathways. It targets Axin—an essential scaffold protein that normally restrains canonical Wnt/β-catenin signaling—for ubiquitination and proteasomal degradation. By reducing Axin levels, RNF146 indirectly amplifies β-catenin signaling, a mechanism implicated in tumorigenesis in cancers such as non-small cell lung cancer and colorectal cancer. In these contexts, RNF146 expression often correlates with increased nuclear β-catenin, enhanced expression of cell cycle regulators, and greater invasive potential. Moreover, post-translational modifications like SUMOylation regulate RNF146’s subcellular localization and activity, further affecting the stability of signaling regulators such as Axin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in signal transduction, RNF146 is critical for cellular stress responses and neuroprotection. By facilitating the degradation of PARylated proteins involved in DNA damage responses, RNF146 contributes to effective DNA repair and prevents PARP1-dependent cell death. This protective function has been demonstrated in models of cerebral ischemia and glutamate excitotoxicity, and its upregulation via estrogen receptor β activation has been shown to shield dopaminergic neurons from degeneration in Parkinson’s disease models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional roles for RNF146 have emerged in the regulation of innate immune signaling and epithelial cell polarity. In antiviral responses, RNF146 promotes the degradation of PARylated VISA (mitochondrial antiviral signaling protein), thereby attenuating excessive type I interferon production. Although RNF146 was identified as a candidate gene in a breast cancer susceptibility locus, detailed mutational analyses in high-risk Ashkenazi cohorts did not support a major role for coding mutations in inherited predisposition. Moreover, RNF146 participates in epithelial polarity by modulating Rab11 activation in coordination with tankyrase, influencing processes such as lumen formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Zhizhi Wang, Gregory A Michaud, Zhihong Cheng, et al. 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