Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2

Abstract

Transforming growth factor-beta1 (TGF-beta1) regulates inflammation and can inhibit activation of the transcription factor NF-kappaB in certain cell types. Here we show that the TGF-beta-induced signaling protein Smad7 bound to TAB2 and TAB3, which are adaptors that link the kinase TAK1 to 'upstream' regulators in the proinflammatory tumor necrosis factor (TNF) signaling pathway. Smad7 thereby promoted TGF-beta-mediated anti-inflammatory effects. The formation of Smad7-TAB2 and Smad7-TAB3 complexes resulted in the suppression of TNF signaling through the adaptors TRAF2, TAB2 and/or TAB3, and TAK1. Furthermore, expression of a transgene encoding Smad7 in mouse skin suppressed inflammation and NF-kappaB nuclear translocation substantially and disrupted the formation of endogenous TRAF2-TAK1-TAB2 and TRAF2-TAK1-TAB3 complexes. Thus, Smad7 is a critical mediator of TGF-beta signals that block proinflammatory TNF signals.

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

“…Second, we provide further evidence for a distinct role of Smad6 from Smad7, although both are anti-inflammatory mediators. Previously, only Smad7 was found to be involved in the negative regulation of TNF-α signalling 5 . In this study, we found that TGF-β1-induced ubiquitin-mediated degradation of MyD88 is dependent on the presence of Smad6, but not Smad7.…”

“…Lentiviruses expressing shRNAs specific for endogenous SMAD7 were previously described 4,5 . To generate shRNAs specific for endogenous SMAD6, SMURF1, SMURF2 and MYD88, double-stranded oligomers containing restriction enzyme sites, a sense sequence, and a loop sequence with its antisense sequence were designed and cloned into AgeI and EcoRI sites of the pLKO-puro vector (Clontech).…”

“…TGF-β has a pivotal role in anti-inflammatory cellular responses where the inhibitory Smads (I-Smads), Smad6 and Smad7, act as important mediators by negatively regulating interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) and tumor necrosis factor-alpha (TNF-α) signals [3][4][5] . I-Smads were originally identified as antagonist proteins of TGF-β/bone morphogenic protein signalling that recruit the HECT E3 ubiquitin ligases Smad ubiquitin regulatory factor 1 (Smurf1) and Smurf2 (refs 6-11), and accumulating evidence indicates that the I-Smads also have roles mediating cross-talk between TGF-β and other signalling pathways 4,5,[12][13][14] .…”

Temporal Smad7 Transgene Induction in Mouse Epidermis Accelerates Skin Wound Healing

“…8 We have shown that keratinocyte-specific Smad7 overexpression causes a reduction in keratinocyte-produced inflammatory cytokines. 13 To determine whether this Smad7 function af- role in wound healing, 27,28 were still present ( Figure 5A). Similar changes lasted till day 9 after wounding; thereafter, leukocyte infiltration was significantly reduced to normal level in either control or Smad7 tg skin (not shown).…”

“…Additionally, the effect of Smad7 may not always be explained by its role in TGF␤ signaling. For instance, Smad7 also interacts with components of the Wnt/␤-catenin 12 and the tumor necrosis factor-␣/nuclear factorkappa B (NF-B) 13 families.…”