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. Author manuscript; available in PMC: 2016 Aug 1.
Published in final edited form as: Exp Hematol. 2015 Jul 2;43(8):587–598. doi: 10.1016/j.exphem.2015.05.016

Figure 2. Overview of cell-intrinsic TLR activation in MDS HSPC cells.

Figure 2

Toll-like receptor (TLR) and IL-1 receptor (IL1R) on HSPC recruit MyD88 and IRAK4, which initiate the assembly of the Myddosome complex. TIRAP can also increase the efficiency of Myddosome assembly by binding MyD88. IRAK4, a serine/threonine kinase, activates IRAK2 and/or IRAK1 through IRAK4-dependent phosphorylation. IRAK1 associates with an E3 Ub ligase, TRAF6, which mediates activation of NF-kB (IKKα/β/γ complex) and MAPK (TAB2/TAB3/TAK1) through K63-linked Ub chains. TRAF6 can also regulate other proteins (indicated by “?”) that may contribute to immune signaling and MDS. miR-146a suppresses IRAK1 and TRAF6 protein expression by direct binding at 3′UTR sites within IRAK1 and TRAF6 mRNAs. A20 suppresses TRAF6 by de-ubiquitinating TRAF6 K63 linkages. Reduced levels of miR-146a or A20 result in increased IRAK1/TRAF6-mediated signaling, impaired HSPC function, and altered myeloid differentiation. The red boxes represent molecules that are overexpressed/activated in MDS. The green boxes represent molecules that are deleted/downregulated in MDS.