{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CYRI (also known as FAM49B) is emerging as a multifunctional regulator that modulates Rac1‐dependent actin cytoskeletal dynamics, thereby impacting immune activation, host–pathogen interactions, and cancer progression. For example, in T lymphocytes, CYRI binds the active form of Rac1 through a conserved domain and functions as a negative regulator; loss of CYRI/FAM49B leads to hyperactivation of T cells following T cell receptor stimulation because of enhanced Rac1 activity and subsequent cytoskeletal reorganization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In pancreatic ductal adenocarcinoma, CYRI localizes to mitochondria where it regulates mitochondrial fission and limits reactive oxygen species generation—processes that suppress tumor cell proliferation and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of infectious diseases, CYRI plays a protective role; by binding Rac1, it dampens signaling that would otherwise promote actin-dependent processes such as macropinocytosis, phagocytosis, and cell migration. This attenuation of Rac1‐driven cytoskeletal changes is critical for restricting bacterial entry and dissemination in infections caused by pathogens such as Salmonella, Mycobacterium tuberculosis, and Listeria monocytogenes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Altered expression of CYRI is also evident in noninfectious disease settings. In endometriosis, for instance, downregulation of FAM49B in omental fat has been documented and linked with concomitant changes in proteinases and environmental chemical exposures."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, in hepatic ischemia/reperfusion injury, upregulation of microRNA-22 targets CYRI, leading to reduced CYRI levels and enhanced inflammatory signaling, an effect that underlines its role in modulating inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, in other cancer types such as hepatocellular carcinoma, elevated expression of FAM49B has been associated with poor prognosis and an immunosuppressive tumor microenvironment, highlighting that the role of CYRI/FAM49B can be context-dependent."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Overall, the collective findings indicate that CYRI/FAM49B functions primarily as a modulator of Rac1 signaling, acting to restrain excessive actin polymerization—thereby controlling T cell activation, limiting pathogen uptake, and influencing tumor cell behavior in a manner that depends on the cellular and disease context.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wanjing Shang, Yong Jiang, Michael Boettcher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1801340115"}], "href": "https://doi.org/10.1073/pnas.1801340115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29632189"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29632189"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "M S Chattaragada, C Riganti, M Sassoe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FAM49B, a novel regulator of mitochondrial function and integrity that suppresses tumor metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2017.358"}], "href": "https://doi.org/10.1038/onc.2017.358"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29059164"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29059164"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kyoko E Yuki, Hadir Marei, Evgenij Fiskin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CYRI/FAM49B negatively regulates RAC1-driven cytoskeletal remodelling and protects against bacterial infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Microbiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41564-019-0484-8"}], "href": "https://doi.org/10.1038/s41564-019-0484-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31285585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31285585"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Katherine E Williams, Olga Miroshnychenko, Eric B Johansen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "FAM49B, restrained by miR-22, relieved hepatic ischemia/reperfusion injury by inhibiting TRAF6/IKK signaling pathway in a Rac1-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molimm.2022.01.015"}], "href": "https://doi.org/10.1016/j.molimm.2022.01.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35131594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35131594"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Feng Xu, Jionghuang Chen, Dihua Huang "}, {"type": "b", "children": [{"type": "t", "text": "Pan-cancer analysis identifies FAM49B as an immune-related prognostic maker for hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cancer (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/jca.65421"}], "href": "https://doi.org/10.7150/jca.65421"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34976189"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34976189"}]}]}]}