{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRIM5 proteins are critical intrinsic restriction factors that block retroviral infection immediately after virus entry. Through their multidomain structure—including a RING domain, B‐box 2, coiled‐coil region, and a C‐terminal SPRY/B30.2 domain—they directly recognize incoming viral capsid lattices in a species‐specific manner. This recognition triggers an early block by accelerating viral uncoating and impeding reverse transcription, thereby preventing productive infection. Variations in the SPRY domain, often resulting from minimal amino acid differences or genetic polymorphisms, underlie differential antiviral potency observed among primate TRIM5 variants."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond direct capsid recognition, TRIM5 proteins function as E3 ubiquitin ligases that self‐ubiquitinate and coordinate the recruitment of cellular degradation machinery. This ubiquitination, which involves specific conjugating enzymes to elaborate Lys63-linked ubiquitin chains, not only marks TRIM5 for proteasome-dependent turnover but also amplifies innate immune signaling through activation of kinases such as TAK1 and transcription factors including NF-κB and AP-1. In some cell types, TRIM5 additionally acts as a selective autophagy receptor that, when engaged via lectin-mediated uptake of viral particles, channels the incoming capsid protein into autophagic degradation. Collectively, these activities support a dual role for TRIM5—in both directly restricting retroviral replication and in shaping downstream innate immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic studies have further revealed that TRIM5 proteins assemble into higher-order oligomeric arrays—often adopting hexagonal lattice geometries that closely match the organization of the retroviral capsid. This lattice formation enhances avidity and the efficiency of capsid binding, thus reinforcing restriction. Moreover, naturally occurring polymorphisms and chimeric constructs (such as TRIM5-CypA fusions) modulate antiviral specificity and potency, offering insights into interspecies differences in retroviral susceptibility as well as novel avenues for antiviral gene therapy. Remarkably, recent findings even extend the antiviral spectrum of TRIM5 to include certain flaviviruses, illustrating its broad plasticity in innate immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Matthew Stremlau, Christopher M Owens, Michel J Perron, et al. 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