{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Interferon‐inducible protein 35 (IFI35, also known as IFP35) is a multifaceted modulator of innate immune signaling whose functions have been revealed in diverse experimental systems. Intracellularly, IFI35 acts as a negative regulator of antiviral responses by modulating the activation status of key RNA sensors. For example, in vesicular stomatitis virus (VSV) infection, overexpression of IFI35 suppresses interferon‐β and interferon‐stimulated gene (ISG) promoter activity—effects that are reversed by its depletion—via direct interaction with the retinoic acid–inducible gene I (RIG‐I), thereby impairing RIG‐I dephosphorylation and promoting its proteasome‐mediated degradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In a related viral context, studies with foamy virus models indicate that IFI35, through cooperation with its binding partner Nmi, interferes with viral transcriptional activation and favors viral latency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its intracellular roles, IFI35 can be released by activated macrophages and function as a damage‐associated molecular pattern (DAMP). In this extracellular context, IFI35 engages the Toll‐like receptor 4 (TLR4)/NF‐κB pathway to promote the secretion of proinflammatory cytokines, thereby exacerbating inflammatory responses in conditions such as septic shock and liver injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In neural and glial models, attenuation of IFI35 expression enhances type I interferon production and downstream STAT1 signaling, further underscoring its role in tempering robust innate immune activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, IFI35 is inducible in other cell types such as mesangial cells where TLR3 stimulation upregulates its expression, contributing to the maintenance of antiviral mediator levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Its functional interactions with partner proteins also appear critical for its activity; for instance, IFI35 binds to Nmi and its stability is modulated by CKIP‐1, while the E3 ubiquitin ligase Trim21 can disrupt the inhibitory IFI35–Nmi complex by specifically ubiquitinating Nmi."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings support a model in which IFI35 plays a dual role in antiviral immunity and inflammation by (i) dampening excessive interferon responses through modulation of RIG‐I and its associated signaling complexes, and (ii), when secreted, acting as a proinflammatory DAMP via TLR4 engagement. This multifunctionality positions IFI35 as an important regulatory node in the innate immune system, with potential implications for viral infections, autoimmune conditions, and inflammatory diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anshuman Das, Phat X Dinh, Debasis Panda, et al. 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