{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNote that none of the provided abstracts describe OR4K3. Instead, they focus on the functions of ICA69 (and, in one case, a related protein ICA1) and its binding partner PICK1 in diverse physiological and pathological settings. In pancreatic beta cells, ICA69 forms heteromeric BAR‐domain complexes with PICK1 to regulate the formation and maturation of insulin secretory granules. Perturbations in this complex are linked to reduced insulin production, hyperglycemia, and altered immune tolerance due to defective thymic expression, thus contributing to autoimmunity in type 1 diabetes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies highlight a key role for ICA69 in the nervous system, where it modulates synaptic plasticity and inflammatory pain. By interacting with PICK1, ICA69 participates in regulating the trafficking and phosphorylation state of glutamate receptor subunits (such as GluR2), with its deficiency leading to reduced PICK1 levels, enhanced receptor internalization, and increased pain hypersensitivity. These interactions are central to both the natural processing of pain signals and the therapeutic effects of interventions like electroacupuncture."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in the endocrine and nervous systems, ICA69 is implicated in systemic autoimmunity and tissue regeneration. Reduced thymic expression of ICA69 is linked to insufficient negative selection of autoreactive T cells, contributing to multi‐organ autoimmune responses, while its upregulation in hepatocytes following partial hepatectomy underlines a role in liver regeneration—acting, at least in part, through modulation of TGFβ signaling. Finally, decreased expression of a related antigen, ICA1, in the brain has been observed in Alzheimer’s disease, suggesting that the ICA protein family may broadly influence immune regulation, cell trafficking, and neural function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shawn Winer, Igor Astsaturov, Roger Gaedigk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ICA69(null) nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.168.1.475"}], "href": "https://doi.org/10.4049/jimmunol.168.1.475"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11751995"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11751995"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Samantha M Bonner, Susan L Pietropaolo, Yong Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.319020"}], "href": "https://doi.org/10.1074/jbc.M111.319020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22447927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22447927"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mian Cao, Zhuo Mao, Chuen Kam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PICK1 and ICA69 control insulin granule trafficking and their deficiencies lead to impaired glucose tolerance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.1001541"}], "href": "https://doi.org/10.1371/journal.pbio.1001541"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23630453"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23630453"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Zhen Wang, Ya-Nan Wang, Cheng-Long Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "C-terminal domain of ICA69 interacts with PICK1 and acts on trafficking of PICK1-PKCα complex and cerebellar plasticity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0083862"}], "href": "https://doi.org/10.1371/journal.pone.0083862"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24358315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24358315"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Qian-Jun Li, Zhen Wang, Yong-Xing Yao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of ICA69 potentiates long-lasting hyperalgesia after subcutaneous formalin injection into the mouse hindpaw."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurochem Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11064-014-1503-z"}], "href": "https://doi.org/10.1007/s11064-014-1503-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25547463"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25547463"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kunyuan Han, Anqi Zhang, Yunchang Mo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Islet-cell autoantigen 69 mediates the antihyperalgesic effects of electroacupuncture on inflammatory pain by regulating spinal glutamate receptor subunit 2 phosphorylation through protein interacting with C-kinase 1 in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pain (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/j.pain.0000000000001450"}], "href": "https://doi.org/10.1097/j.pain.0000000000001450"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30699097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30699097"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yong Fan, Giulio Gualtierotti, Asako Tajima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Compromised central tolerance of ICA69 induces multiple organ autoimmunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Autoimmun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jaut.2014.07.001"}], "href": "https://doi.org/10.1016/j.jaut.2014.07.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25088457"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25088457"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Linjie Chen, Fei Tao, Yangyang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Islet-cell autoantigen 69 accelerates liver regeneration by downregulating Tgfbr1 and attenuating Tgfβ signaling in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/1873-3468.13859"}], "href": "https://doi.org/10.1002/1873-3468.13859"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32531799"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32531799"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Liangye Ji, ZiJun Meng, Xiangjun Dong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ICA1 affects APP processing through the PICK1-PKCα signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "CNS Neurosci Ther (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cns.14754"}], "href": "https://doi.org/10.1111/cns.14754"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38884369"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38884369"}]}]}]}