{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nReceptor transporter protein 4 (RTP4) functions as a specialized chaperone that facilitates the maturation and cell surface trafficking of G protein–coupled receptor (GPCR) complexes. Notably, RTP4 protects mu–delta opioid receptor heterodimers from ubiquitination and degradation, thereby increasing their membrane abundance and modulating opioid signaling and analgesia. Chronic morphine exposure robustly upregulates RTP4 expression in brain regions such as the hypothalamus, leading to enhanced receptor delivery and contributing to the development of antinociceptive tolerance. Moreover, RTP4 is also inducible by immune stimuli, as evidenced by its upregulation during malaria parasite infection where it negatively regulates TBK1 signaling and the ensuing interferon response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "In addition to its regulatory role in opioid receptor biology and inflammatory signaling, RTP4 exhibits a broad antiviral capacity. The protein is potently induced in response to interferon and, via its conserved zinc finger motifs, can bind directly to viral genomic RNA. This interaction inhibits the synthesis of viral RNA and protein production—a mechanism demonstrated in studies of human coronaviruses (including SARS-CoV‑2 and its Omicron variants) as well as in infections with rabies virus, where RTP4 expression correlates with reduced viral replication and improved survival outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fabien M Décaillot, Raphael Rozenfeld, Achla Gupta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0804106105"}], "href": "https://doi.org/10.1073/pnas.0804106105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18836069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18836069"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wakako Fujita, Mini Yokote, Ivone Gomes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of an Opioid Receptor Chaperone Protein, RTP4, by Morphine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.118.112987"}], "href": "https://doi.org/10.1124/mol.118.112987"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30348895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30348895"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiao He, Alison W Ashbrook, Yang Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RTP4 inhibits IFN-I response and enhances experimental cerebral malaria and neuropathology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2006492117"}], "href": "https://doi.org/10.1073/pnas.2006492117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32709745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32709745"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Wakako Fujita, Hitoshi Uchida, Masashi Kawanishi, et al. 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