{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAlthough none of the provided abstracts mention TANGO6, they collectively describe the function of the inflammasome sensor pyrin—a protein encoded by MEFV whose regulation is fundamental for innate immune responses. Pyrin detects alterations induced by bacterial toxins (especially those that inactivate RhoA) and coordinates the assembly of an inflammasome complex with the adaptor ASC. This complex then drives caspase-1 activation, the maturation of proinflammatory cytokines such as IL-1β, and the execution of pyroptotic cell death. Moreover, pyrin can modulate apoptosis independently of IL-1β pathways and engage in competitive binding with caspase-1 for ASC, thereby finely tuning the inflammatory output."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPathogens have evolved mechanisms to subvert pyrin’s protective functions. For instance, virulence factors from pathogens like Yersinia, such as YopM, exploit host kinases (PRK1/PRK2) to phosphorylate pyrin and thereby inhibit its inflammasome activation. In parallel, studies have revealed that multiple innate sensors—including AIM2 and ZBP1—can coordinate with pyrin to form a multifunctional “PANoptosome” that channels inflammatory cell death (PANoptosis) to secure host defense. These pathogen-directed, as well as host-mediated, modulations of pyrin activity contribute to disease states, including hereditary autoinflammatory disorders and inflammatory bowel diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, pyrin activity is subject to intricate regulation by upstream signaling pathways. TNF signaling, for instance, controls pyrin expression and directly modulates inflammasome activation, influencing systemic inflammation and specific tissue pathologies. Similarly, components of the cell death machinery, such as RIPK3, and signaling trajectories involving mTOR and MAPK pathways, critically determine the transcriptional and post‐translational regulation of pyrin. Complementing the role of kinases in inhibiting pyrin, phosphoprotein phosphatases such as PP2A actively dephosphorylate pyrin to enable inflammasome assembly. Together, these molecular circuits illustrate the complex balance maintained by pyrin to promote host defense while restraining hyperinflammation, insights that may pave the way for novel therapeutic strategies against autoinflammatory disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jae Jin Chae, Hirsh D Komarow, Jun Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1097-2765(03)00056-x"}], "href": "https://doi.org/10.1016/s1097-2765(03"}, {"type": "t", "text": "00056-x) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12667444"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12667444"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Pamela R Hesker, MyTrang Nguyen, Martina Kovarova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic loss of murine pyrin, the Familial Mediterranean Fever protein, increases interleukin-1β levels."}]}, {"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.0051105"}], "href": "https://doi.org/10.1371/journal.pone.0051105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23226472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23226472"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lawton K Chung, Yong Hwan Park, Yueting Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2016.07.018"}], "href": "https://doi.org/10.1016/j.chom.2016.07.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27569559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27569559"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Deepika Sharma, Ankit Malik, Clifford S Guy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2017.11.276"}], "href": "https://doi.org/10.1053/j.gastro.2017.11.276"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29203393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29203393"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "SangJoon Lee, Rajendra Karki, Yaqiu Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-021-03875-8"}], "href": "https://doi.org/10.1038/s41586-021-03875-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34471287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34471287"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Deepika Sharma, Ankit Malik, Clifford Guy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI121372"}], "href": "https://doi.org/10.1172/JCI121372"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30457980"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30457980"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Deepika Sharma, Ankit Malik, Arjun Balakrishnan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK3 Promotes "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "Mefv"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Expression and Pyrin Inflammasome Activation via Modulation of mTOR Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.2000244"}], "href": "https://doi.org/10.4049/jimmunol.2000244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32989095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32989095"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Haleema S Malik, Flora Magnotti, Nicole A Loeven, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphoprotein phosphatase activity positively regulates oligomeric pyrin to trigger inflammasome assembly in phagocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "mBio (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/mbio.02066-23"}], "href": "https://doi.org/10.1128/mbio.02066-23"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37787552"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37787552"}]}]}]}