{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTICAM2 (also known as TRAM) is a Toll‐like receptor adaptor that mediates the MyD88‐independent branch of TLR4 signaling. Early studies identified TICAM2 as a novel bridging adaptor that physically links TLR4 to TICAM1/TRIF, thereby facilitating lipopolysaccharide–induced activation of interferon regulatory factor‐3 and subsequent type I interferon production. Moreover, TLR4 activation occurs in sequential phases with plasma membrane‐located MyD88–dependent signals preceding endosomal TICAM2–TICAM1 signaling, underscoring TICAM2’s essential role as a sorting adaptor once TLR4 is internalized."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and binding studies have further delineated the molecular underpinnings of TICAM2 function. Detailed analyses reveal that TICAM2 contains a TIR domain capable of homotypic interactions that provide a scaffold for recruiting TICAM1 and other signaling molecules. For example, TICAM2 has been shown to directly interact with MyD88 in specific cytokine (e.g., IL-18) signaling contexts and to engage TRAF6 via a putative binding motif, thereby modulating NF-κB–dependent responses. Critical acidic motifs within TICAM2’s TIR domain—such as the E87/D88/D89 and D91/E92 clusters—are vital for its membrane anchoring and self-aggregation, which are prerequisites for its function in endosomal TLR4 signaling and subsequent IRF3 activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its pivotal role in TLR4 signaling, TICAM2 also contributes to the function of other TLRs. Evidence indicates that in TLR7 signaling, TICAM2 cooperates with MyD88 to promote type I interferon production during antiviral responses. In addition, genetic studies have associated TICAM2 polymorphisms with susceptibility to tuberculosis, underscoring its broader importance in host defense. Collectively, these findings emphasize that TICAM2 acts as a versatile adaptor that orchestrates endosomal signaling events essential for both antiviral immunity and regulation of inflammatory cytokine production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroyuki Oshiumi, Miwa Sasai, Kyoko Shida, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni1569"}], "href": "https://doi.org/10.1038/ni1569"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18297073"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18297073"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hidenori Ohnishi, Hidehito Tochio, Zenichiro Kato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0038423"}], "href": "https://doi.org/10.1371/journal.pone.0038423"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22685567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22685567"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yoshiaki Enokizono, Hiroyuki Kumeta, Kenji Funami, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Identification of a Regulatory Acidic Motif as the Determinant of Membrane Localization of TICAM-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1402628"}], "href": "https://doi.org/10.4049/jimmunol.1402628"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26408662"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26408662"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kenji Funami, Misako Matsumoto, Hiroyuki Oshiumi, et al. 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