Previous experimental and clinical studies and the initial findings of this pilot study now elucidate a path toward the clinical use of micro-structured β-TCP bone substitute for repair of the alveolar cleft.

Edited by Xiao-Fan WangGene-specific transcription factors (GSTFs) control gene transcription by DNA binding and specific protein complex recruitment, which regulates promoter accessibility for transcription initiation by RNA polymerase II. Mutations in the GSTFs Suppressor of Mothers Against Decapentaplegic 2 (SMAD2) and SMAD4 are frequently associated with colon and rectal carcinomas. These proteins play an important role in bone morphogenic protein (BMP) and transforming growth factor ␤ (TGF-␤) signaling pathways controlling cell fate and proliferation. To study the protein interactome of the SMAD protein family we generated a quantitative proteomics pipeline that allows for inducible expression of GFP-tagged SMAD proteins followed by affinity purification and quantitative mass spectrometry analysis. Data are available via ProteomeXchange with identifier PXD004529. The nuclear importin IPO5 was identified as a novel interacting protein of SMAD1. Overexpression of IPO5 in various cell lines specifically increases nuclear localization of BMP receptor-activated SMADs (R-SMADs) confirming a functional relationship between IPO5 and BMP but not TGF-␤ R-SMADs. Finally, we provide evidence that variation in length of the lysine stretch of the nuclear localization sequence is a determinant for importin specificity.Transcription regulation is a tightly controlled process that is influenced by the binding of gene-specific transcription factors (GSTFs) 2 to specific DNA elements (1). These GSTF families are highly heterogeneous, spanning several hundreds of proteins like the C 2 H 2 -type zinc fingers (2) to the eight members of the SMAD protein family. Binding of GSTFs to DNA elements mediates recruitment of multisubunit co-activator complexes like SET/MLL, Mediator, TFIID, or the BAF remodeler, each of which can specifically affect the chromatin microenvironment resulting in alteration of gene transcriptional states. Cancer genome-wide association studies have shown that GSTFs and chromatin-associated proteins are often mutated in various solid tumors types (3-5). In particular, mutations in SMAD2 and SMAD4 have been frequently associated with colon and rectal carcinomas (5.7 and 9.8%, respectively) (3). The eight SMAD family members can be divided into the R-SMADs (SMAD1/2/3/5/9), I-SMADs (SMAD6/7), and Co-SMAD (SMAD4) (Fig. 1A). R-SMADs can additionally be subdivided into BMP (SMAD1/5/9) and TGF-␤ (SMAD2/3) subclasses depending on the ligand activating.SMAD signaling starts with the activation of the anaplastic lymphoma kinase type II receptors by the binding of the BMP or TGF-␤ cytokines. Activation of type II receptors recruits and phosphorylates anaplastic lymphoma kinase type I receptors, which in turn activate the R-SMADs by phosphorylating the SSXS residues in the C-terminal domain (6 -8). In basal conditions the SMADs shuttle constantly between the cytoplasm and the nucleus (9) via interaction with the nucleoporins (10). After receptor-mediated R-SMAD activation, an import protein is required for their nuclear...

Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR-31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31-induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

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