Page 326 - Williams Hematology ( PDFDrive )

300 Part IV: Molecular and Cellular Hematology Chapter 20: Innate Immunity 301

Figure 20–6. The nucleotide-binding oligomerization domain (NOD) 1/2 signaling pathways. Upon sensing PGN-derived motifs in the cyto-
sol (γ-d-glutamyldiaminopimelic acid [DAP] and muramyl dipeptide [MDP]), NOD1 and NOD2 oligomerize and form complexes with the serine/
threonine kinase RICK2. Signaling through tumor necrosis factor receptor–associated factors (TRAFs, which are E3 ubiquitin ligases) results in K63
ubiquitination (chained circles) of RICK2, and transforming growth factor-β–activating kinase (TAK)-1 recruitment. Activation of the TAK-1 complex
leads to IκB kinase (IKK) and MKK activation, resulting in signaling cascades similar to those activated in response to TLR ligands. Caspase activating
and recruitment domain (CARD) 9 is important for p38 activation downstream of NOD2. NOD-like receptor (NLR) protein domains shown are the
same as in Fig. 20–4. Phosphorylation events are represented by P-labeled circles. Abbreviations are as used in the text.

MDA5 have more proximal CARD domains involved in signaling, Although TLR3 can detect dsRNA and its synthetic analogue
whereas LGP2 does not. On this basis it was initially believed that LGP2 poly I:C, the dominant sensor of poly I:C (long polymers in particular)
90
93
might have an inhibitory function. However, it appears to contribute in vivo is MDA5 ; shorter poly I:C polymers are better detected by
to sensing in a positive manner, and may augment RIG-I and MDA5 RIG-I. RIG-I is able to form stable complexes with dsRNA molecules
signaling. 89,91,92 containing blunt ends or 5′-overhangs, while dsRNA with 3′-overhangs

Kaushansky_chapter 20_p0293-0306.indd 301 9/17/15 5:52 PM