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. 2018 Dec 13;39(5):1447–1484. doi: 10.1002/med.21557

Figure 2.

Figure 2

Canonical and noncanonical signaling pathways of NOD1 and NOD2. A, B, NF‐κB and MAPK signaling pathways. NOD1 and NOD2 recognize bacterial PGN fragments, iE‐DAP and MDP, respectively. After ligand recognition, NODs undergo conformational changes and self‐oligomerization through homophilic CARD‐CARD interactions, allowing the recruitment and activation of the adaptor protein RIPK2. In an established protein complex, RIPK2 is polyubquitinated by TRAFs and cIAPs, allowing the recruitment of polyubiquitinated NEMO or TAK1 to the established protein complex. On one hand, NEMO triggers activation of the NF‐κB pathway by phosphorylation of IκB resulting in release NF‐κB transcription factor. The latter translocates to the nucleus where causes induction of pro‐inflammatory genes. On the other hand, TAK1 recruits TAB1/2/3 activating both NF‐κB and MAPK pathway (JNK, ERK, and p38). Activated MAPKs translocate to the nucleus and activate AP‐1 transcription factor resulting transcription of genes involved in inflammatory response. C, Apoptosis pathway. NODs have been reported to interact with the apoptotic pathway indirectly through IAP family of proteins (cIAP1, cIAP2, and XIAP) and proapoptotic protein Bid. D, Inflammasome activation. NODs associate with several other NLRs (NLRP1 and NLRP3) to form inflammasome protein complexes. After detection of their cognate ligand, NLRs interact with ASC protein and procaspase‐1, resulting in formation of inflammasomes. Once formed, inflammasomes activate procaspase‐1, which in turn proteolytically processes pro‐inflammatory cytokines IL‐1β and IL‐18. E, Autophagy. Activated NODs recruit the autophagy protein ATG16L1 to the cell membrane and facilitate the formation of autophagosome around invading bacteria. F, Antiviral response. Viral ssRNA activates NOD2, which translocates to the mitochondria and supposedly binds to MAVS. This promotes formation of a complex with TBK1 and IKKα, which enables activation of interferon regulatory factor (IRF) 3 resulting in production of IFN type I. ASC, apoptosis‐associated speck‐like protein containing caspase recruitment domain; CARD, caspase recruitment domain; cIAP, cellular inhibitor of apoptosis protein; ERK, extracellular signal‐regulated kinase; IAP, inhibitor of the apoptosis; iE‐DAP, d‐glutamyl‐meso‐diaminopimelic acid; IFN, interferon; IKK, IκB kinase; IκB, protein inhibitor of NF‐κB; IL, interleukin; JNK, c‐Jun N‐terminal kinase; NOD, nucleotide‐binding oligomerization domain; NF‐κB, nuclear factor κB; MAPK, mitogen‐associated protein kinase; MAVS, mitochondrial antiviral signaling; MDP, muramyl dipeptide; NEMO, nuclear factor κB essential modulator; NLRs, nucleotide‐binding oligomerization domain‐like receptors; PGN, peptidoglycan; RIPK2, receptor‐interacting serine/threonine‐protein kinase 2; TAB, transforming growth factor binding protein; TAK1, transforming growth factor β‐activated kinase 1; TBK1, TRAF‐associated nuclear factor‐κB activator–binding kinase 1; TRAFs, tumor necrosis factor receptor–associated factors; XIAP, X‐linked inhibitor of apoptosis protein [Color figure can be viewed at wileyonlinelibrary.com]