{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRNF13 is an E3 ubiquitin ligase localized primarily to the endoplasmic reticulum and Golgi membranes that plays a multifaceted role in cancer biology. Over‐expression of RNF13 has been observed in pancreatic ductal adenocarcinoma, where its ubiquitin ligase activity is required for promoting invasive cell behavior via matrix metalloproteinase‐9 activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, genetic screens have revealed that RNF13 is a critical mediator of endoplasmic reticulum (ER) stress–induced apoptosis—its over‐expression triggers JNK activation via the IRE1α–TRAF2 signaling axis, whereas its knockdown confers resistance to apoptotic stimuli."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, pathogenic RNF13 variants associated with infantile neurodegeneration enhance IRE1α-dependent stress signaling and apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In the context of hematological malignancies, a circular RNA derived from the RNF13 transcript (circRNF13) has been linked to acute myeloid leukemia and may serve as a prognostic marker"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while in myocardial tissue, RNF13—directly targeted by miR-32-3p—regulates ER stress–induced cardiomyocyte apoptosis and contributes to plaque stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in modulating apoptotic and oncogenic pathways, RNF13 is crucial for proper intracellular vesicle trafficking. Its endosomal localization depends on intact structural elements—including the RING and PA domains—and mutations in these regions, identified in human tumors, disrupt endolysosomal dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, under specific stimuli such as PMA or ionomycin treatment, RNF13 escapes proteolysis and is redirected from recycling endosomes to the inner nuclear membrane."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Missense variants linked to developmental and epileptic encephalopathies further perturb endolysosomal trafficking by altering the size of endosomal vesicles and compromising interactions with the AP-3 complex."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In macrophages, lysosomally localized RNF13 directs K48-linked ubiquitination of LAMP-1, thereby delaying lysosome maturation and enhancing Toll-like receptor–mediated inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional insight comes from studies of RNF13 homologs in non-mammalian models; for example, the chicken RING zinc finger protein (C-RZF) contains similar structural motifs—including a leucine zipper and nuclear localization signal—and is predominantly localized in the nucleus, suggesting roles in DNA binding and transcription regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Remarkably, in humans, truncating variants in the terminal exon of RNF13 that escape nonsense-mediated decay have been associated with a constellation of neurodevelopmental defects—namely congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive—supporting a gain-of-function mechanism in disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qiang Zhang, Yunxiao Meng, Lei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNF13: a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2008.285"}], "href": "https://doi.org/10.1038/cr.2008.285"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18794910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18794910"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Muhammad Arshad, Zhongde Ye, Xiaofeng Gu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNF13, a RING finger protein, mediates endoplasmic reticulum stress-induced apoptosis through the inositol-requiring enzyme (IRE1α)/c-Jun NH2-terminal kinase pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.368829"}], "href": "https://doi.org/10.1074/jbc.M112.368829"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23378536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23378536"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Simon Edvardson, Claudia M Nicolae, Grace J Noh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2018.11.018"}], "href": "https://doi.org/10.1016/j.ajhg.2018.11.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30595371"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30595371"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Rong Zhang, Yingchun Li, Hongtao Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Regulation of circRNA RNF13/miRNA-1224-5p Axis Promotes the Malignant Evolution in Acute Myeloid Leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2020/5654380"}], "href": "https://doi.org/10.1155/2020/5654380"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33083473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33083473"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Dajun Huang, Yang Liu, Le Gao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-32-3p Regulates Myocardial Injury Induced by Microembolism and Microvascular Obstruction by Targeting RNF13 to Regulate the Stability of Atherosclerotic Plaques."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cardiovasc Transl Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12265-021-10150-8"}], "href": "https://doi.org/10.1007/s12265-021-10150-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34185281"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34185281"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jesper R van Dijk, Yasuo Yamazaki, Ruth H Palmer "}, {"type": "b", "children": [{"type": "t", "text": "Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20131067"}], "href": "https://doi.org/10.1042/BJ20131067"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24387786"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24387786"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jeffrey P Bocock, Stephanie Carmicle, Egbert Madamba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear targeting of an endosomal E3 ubiquitin ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Traffic (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0854.2010.01060.x"}], "href": "https://doi.org/10.1111/j.1600-0854.2010.01060.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20230530"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20230530"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Valérie C Cabana, Antoine Y Bouchard, Audrey M Sénécal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells10113063"}], "href": "https://doi.org/10.3390/cells10113063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34831286"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34831286"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Wei Liu, Yuyang Wang, Shuo Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "E3 Ubiquitin Ligase RNF13 Suppresses TLR Lysosomal Degradation by Promoting LAMP-1 Proteasomal Degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Sci (Weinh) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/advs.202309560"}], "href": "https://doi.org/10.1002/advs.202309560"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39031743"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39031743"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "P Tranque, K L Crossin, C Cirelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of a RING zinc finger gene (C-RZF) expressed in chicken embryo cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (1996)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.93.7.3105"}], "href": "https://doi.org/10.1073/pnas.93.7.3105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "8610176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/8610176"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Alan Taylor, Pawan S Kashyape, Ruchi Jain, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterozygous gain of function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.63390"}], "href": "https://doi.org/10.1002/ajmg.a.63390"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37668308"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37668308"}]}]}]}