{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRIPK2—also known as RICK or CARDIAK—is a CARD‐containing serine/threonine kinase that functions as an essential signal transducer linking both the innate and adaptive immune systems. It is rapidly recruited into Toll‐like receptor (TLR), interleukin‐1/18 receptor, and T‐cell receptor complexes, thereby promoting NF‑κB activation, cytokine production, and T‑cell proliferation and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn its canonical role downstream of the intracellular sensors NOD1 and NOD2, RIPK2 is rapidly modified by lysine‑63‐linked polyubiquitination—a process that is triggered upon recognition of bacterial peptidoglycan fragments. This modification not only enables RIPK2 to recruit downstream effector kinases such as TAK1 and components of the IKK complex but also is critical for membrane recruitment in epithelial cells, thereby orchestrating timely NF‑κB signaling and proinflammatory cytokine responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRIPK2’s kinase activity—including its ability to autophosphorylate on both serine and tyrosine residues—is indispensable for optimal signal propagation. Tyrosine phosphorylation (for example on Tyr 474) plays a decisive role in efficient NOD2 signaling and cytokine release, while its autophosphorylation on residues such as Ser 176 underlies its catalytic activation. These phosphorylation events, together with subsequent dimerization, serve as key regulatory checkpoints in RIPK2-mediated NF‑κB and MAPK activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural studies have revealed that the CARD domain of RIPK2 is capable of oligomerizing into helical filaments, thereby providing a platform for signal amplification. Interactions between the RIPK2 CARD and the tandem CARDs of NOD1 and NOD2 occur through multiple interfaces (including both type I and type III interactions), and subtle mutations within these interfaces can disrupt downstream NF‑κB activation. Such structural determinants underpin the assembly of the “nodosome” and are critical for propagating immune signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRIPK2 is also pivotal in host defense against microbial pathogens. Its recruitment and activation by NOD1/2 mediate inflammatory and autophagic responses to diverse bacteria—including Gram‑negative organisms such as Fusobacterium nucleatum and Chlamydia trachomatis—and even contribute to epithelial cell responses in cancers of the colorectal region and esophagus. Moreover, certain bacterial pathogens (for example, Porphyromonas gingivalis) can modulate RIPK2 activity to alter downstream signaling, ultimately affecting processes like PD‑L1 upregulation and cytokine secretion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in immune signaling, RIPK2 has been implicated in nonimmune functions and disease pathogenesis. Downregulation of RIPK2 accompanies myogenic differentiation, while in the context of cancer, its overexpression or aberrant activation is associated with chemoresistance in triple‑negative breast cancer and with increased risk in urothelial malignancies. Furthermore, pathogenic insults—from HIV‑1 protease cleavage to hepatitis B e antigen–mediated downregulation—as well as modulation by regulatory proteins like LRRK2 and SHIP‑1, underscore RIPK2’s multifaceted roles in inflammation‐associated pathology and cellular stress responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, post‐translational modifications—such as ubiquitination—further refine RIPK2 function. The conjugation of lysine‑63 polyubiquitin chains and the direct binding of ubiquitin to regions within NOD receptor CARDs serve as a negative feedback mechanism that modulates the strength and duration of RIPK2‐mediated NF‑κB signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Koichi Kobayashi, Naohiro Inohara, Lorraine D Hernandez, et al. 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