Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation

Zhang, Song; Takaku, Motoki; Zou, Liyun; Gu, Ai Di; Chou, Wei-Chun; Zhang, Ge; Wu, Bing; Kong, Qing; Thomas, Seddon Y.; Serody, Jonathan S.; Chen, Xian; Xu, Xiaojiang; Wade, Paul A.; Cook, Donald N.; Ting, Jenny P.-Y.; Wan, Yisong Y.

doi:10.1038/nature24283

Cited by 100 publications

(110 citation statements)

References 30 publications

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“…MSCs can differentiate into osteoblasts and adipocytes, and the differentiation into either cell type is reversely exclusive . In this study, we demonstrate a noncanonical role of Smad4 independent of TGF‐β and BMP signals regarding MSC differentiation, like TGF‐β‐independent functions of Smad4 reported by several groups . Our work revealed that Smad4 is reciprocally involved in osteogenic and adipogenic differentiation in C3H10T1/2 MSC cell line and primary hASCs and modulates the nuclear localization of Taz in all cells used in this study.…”

Section: Discussionsupporting

confidence: 78%

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

et al. 2018

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Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipoosteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-β signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Tazperoxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. STEM CELLS 2019;37:368-381 SIGNIFICANCE STATEMENTAlthough the Smad4 protein has been suggested to act as a common Smad in the transforming growth factor-β (TGF-ß) superfamily signaling pathway in human embryonic stem cells, it has been unclear whether Smad4 has a noncanonical role in adipo-osteogenic differentiation of mesenchymal stem cells (MSCs), independent of the TGF-ß and bone morphogenic protein pathways. The study demonstrated that Smad4 plays a crucial role in the regulation of lineage commitment of the MSCs, including human adipose tissue-derived stem cells, into osteoblasts and adipocytes through modulating the retention of Taz in the nucleus during MSC differentiation. The Smad4 is specific to Taz but not YAP. Therefore, the findings provide new insight into a novel mechanism of the Smad4-Taz axis in adipo-osteogenic differentiation of MSCs and demonstrate a reciprocal role of Smad4 as a positive and negative factor in osteogenesis and adipogenesis of MSCs, respectively.

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Section: Discussionsupporting

confidence: 78%

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

et al. 2018

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“…TGF-β signaling reverses Smad4-mediated suppression of RORγt via a SKI-dependent mechanism. 147 Whether similar mechanisms are underlying TGF-β-induced T RM differentiation remains to be demonstrated. In addition, TGF-β regulates several T cell-related target genes (e.g., Eomes and RORγt) in a Smad2/3-independent manner.…”

Section: Transcriptional Regulation Of Trm Cellsmentioning

confidence: 99%

Tissue-Specific Control of Tissue-Resident Memory T Cells

Liu

Zhang

2018

Crit Rev Immunol

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Tissue-resident memory T (TRM) cells have emerged to be a major component of T cell biology. Recent investigations have greatly advanced our understanding of TRMs. Common features have been discovered to distinguish memory T cells residing in various mucosal and non-mucosal tissues from their circulating counterparts. Given that most organs and tissues contain unique microenvironment, local signal-induced tissue-specific features are tightly associated with the differentiation, homeostasis and protective functions of TRMs. We will discuss the recent advances in TRM field with a special emphasis on the interaction between local signals and TRM cells in the context of individual tissue environment.

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“…For example, genetic repression of TH1 and TH2 cell differentiation was shown to relieve the requirement for TGF-b in IL-6-mediated TH17 induction and, indeed, TH17 cells can be differentiated in vitro by a combination of IL-6, IL-23 and IL-1β (Das et al, 2009;Ghoreschi et al, 2010). Recently, Wan and colleagues revealed that SKI, via SMAD4, transcriptionally repressed Rorc and that TGF-β signaling degraded or modified SKI to relieve the inhibition and promote TH17 cell differentiation in the presence of IL-6 (Zhang et al, 2017). Our studies indicate that SAAs function independently of STAT3 or the SMAD transcription factors, and that they do not regulate SKI degradation (unpublished).…”

Section: Saa-dependent Differentiation Of Pathogenic Th17 Cellsmentioning

confidence: 99%

Serum Amyloid A Proteins Induce Pathogenic T_H17 Cells and Promote Inflammatory Disease

Lee¹,

Hall²,

Kroehling³

et al. 2019

Preprint

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Lymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by RORgt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naïve CD4 + T cells. In the nonpathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss-and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

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Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation

Cited by 100 publications

References 30 publications

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

Tissue-Specific Control of Tissue-Resident Memory T Cells

Serum Amyloid A Proteins Induce Pathogenic T_H17 Cells and Promote Inflammatory Disease

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Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation

Cited by 100 publications

References 30 publications

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells

Tissue-Specific Control of Tissue-Resident Memory T Cells

Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease

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Product

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Serum Amyloid A Proteins Induce Pathogenic T_H17 Cells and Promote Inflammatory Disease