{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNLRP4 is a member of the NOD-like receptor family that has emerged as a multifunctional intracellular regulator. Structural studies of its pyrin domain revealed unique features—such as an atypically long helix α13 and distinct interhelical loops—that differentiate it from other PYD‐containing proteins and underlie selective interaction patterns. In addition, experimental evidence demonstrates that NLRP4 directly binds Beclin1, a key initiator of autophagy, and that its suppression via RNA interference leads to enhanced autophagic flux and improved bactericidal clearance in the context of invasive bacterial infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of immune signaling, NLRP4 exerts a negative regulatory influence on type I interferon and pro‐inflammatory cytokine responses. Specifically, NLRP4 recruits an E3 ubiquitin ligase (DTX4) to catalyze Lys48‐linked polyubiquitination of TBK1, targeting this key kinase for degradation and thereby tempering interferon production. Consistent with this role, studies in cardiac cells have shown that NLRP4 attenuates TBK1/IRF3 and IKK/NF‐κB signaling cascades, reducing the release of cytokines such as TNF‑α, IL‑6, and other mediators implicated in cardiac remodeling. Moreover, in systemic inflammatory disorders and certain cancers, altered NLRP4 expression or mutation correlates with changes in interferon responses—for example, reduced NLRP4 activity can enhance IFN‑α/β production and increase CD8⁺ T cell recruitment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in regulating interferon and inflammatory signaling, NLRP4 also contributes to the control of autophagic processes that are crucial for cellular defense against pathogens. In xenophagy, NLRP4 is rapidly recruited to bacteria-containing vacuoles where it binds ARHGDIA to modulate Rho GTPase–mediated actin dynamics, thereby facilitating the assembly and elongation of autophagosomes required for pathogen clearance. Genetic studies further link NLRP4 variants with clinical phenotypes; for instance, loss-of-function frameshift mutations in NLRP4 have been observed in microsatellite unstable gastrointestinal cancers, and certain single-nucleotide polymorphisms in NLRP4 are associated with increased asthma exacerbation frequency, particularly in smokers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nao Jounai, Kouji Kobiyama, Masaaki Shiina, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.2239"}], "href": "https://doi.org/10.1038/ni.2239"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22388039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22388039"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yong-Gang Lian, Hai-Ying Zhao, Sheng-Ji Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.15243"}], "href": "https://doi.org/10.1111/cas.15243"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34927309"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34927309"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Piero Ruscitti, Onorina Berardicurti, Ilenia Di Cola, et al. 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