Activation of TGF-b/Smad signaling plays a central role in the pathogenesis of tubulointerstitial fibrosis, but the mechanisms underlying the initial interaction of the TGF-b receptor with Smads, leading to their activation, remain unclear. Here, we found that Kindlin-2, an integrin-binding protein, physically mediated the interaction of the TGF-b type I receptor (TbRI) with Smad3 in human kidney tubular epithelial cells. Kindlin-2 bound to TbRI through its FERM domain and to Smad3 through its N terminus. Overexpression of Kindlin-2 increased TGF-b-induced Smad3 activation. Knockdown of Kindlin-2 significantly suppressed the engagement of TbRI with Smad3 and inhibited TGF-b-induced Smad3 activation, as well as the expression of its target genes. Neither transfection of a Kindlin-2 mutant incapable of binding to b1 integrin nor knockdown of b1 integrin influenced the effect of Kindlin-2 on TGF-b1-induced Smad3 activation, indicating that this effect is independent of integrin. Kindlin-2 expression was markedly increased, predominantly in renal tubular epithelial cells, both in the unilateral ureteral obstruction model of kidney fibrosis and in human tissue exhibiting tubulointerstitial fibrosis. Furthermore, in the unilateral ureteral obstruction model, knocking down Kindlin-2 significantly inhibited activation of TGF-b/Smad signaling, decreased the expression of matrix genes, and ameliorated fibrosis. In summary, Kindlin-2 physically interacts with both TbRI and Smad3, promoting the activation of TGF-b/Smad signaling and contributing to the pathogenesis of tubulointerstitial fibrosis. Blockade of Kindlin-2 might be a rational therapeutic strategy for the treatment of fibrotic kidney diseases.

The IL-1 family consists of 11 cytokines, 7 ligands with agonist activity (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and four members with antagonistic activities [IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, IL-38]. Recent articles have described that most members of IL-1 family cytokines are involved in the process of innate and adaptive immunity as well as fibrosis in systemic sclerosis (SSc). IL-1 family gene polymorphisms, abnormal expression of IL-1 and its potential role in the fibrosis process have been explored in SSc. IL-33 and IL-18 have also been discussed in the recent years. IL-33 may contribute to the fibrosis of SSc, while IL-18 remains to be researched to confirm its role in fibrosis process. There is a lack of study on the pathophysiological roles of IL-36, IL-37, and IL-38 in SSc, which might provide us new study area. Here, we aim to give a brief overview of IL-1 family cytokines and discuss their pivotal roles in the pathogenesis of SSc.

BackgroundInsulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC.MethodsCaki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array.ResultsIMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-кB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients.ConclusionIMP3 promotes RCC cell migration and invasion by activation of NF-кB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC.

Highlights d Kindlin-2 mediates MOB1 proteasomal degradation by its E3 ligase praja2 d Kindlin-2 inhibits phosphorylation of YAP by promoting degradation of MOB1 d Kindlin-2 depletion activates the Hippo pathway and alleviates UUO-induced renal fibrosis d Long-lasting Kindlin-2 siRNA shows a therapeutic value in UUO-induced renal fibrosis

Wang et al. unveil a new mechanism by which Src may function as an oncogene. Phosphorylation of FHL1 by Src triggers the translocation of FHL1 to the nucleus, where it regulates the activity of the transcription factor BCLAF1 to promote tumor cell growth and loses the ability to regulate cell adhesion and suppress growth.

Integrin-mediated cellular functions require integrin activation by the proteins Kindlin-2 and Talin. Wei et al. show that the E3 ligase Smurf1 permits precise modulation of integrin-mediated adhesion by interacting with and promoting Kindlin-2 ubiquitination and degradation.

BackgroundEpstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is a distinct molecular subtype of GC with a favorable prognosis. However, the exact effects and potential mechanisms of EBV infection on immune checkpoint blockade (ICB) efficacy in GC remain to be clarified. Additionally, EBV-encoded RNA (EBER) in situ hybridization (ISH), the traditional method to detect EBV, could cause false-positive/false-negative results and not allow for characterizing other molecular biomarkers recommended by standard treatment guidelines for GC. Herein, we sought to investigate the efficacy and potential biomarkers of ICB in EBVaGC identified by next-generation sequencing (NGS).DesignAn NGS-based algorithm for detecting EBV was established and validated using two independent GC cohorts (124 in the training cohort and 76 in the validation cohort). The value of EBV infection for predicting ICB efficacy was evaluated among 95 patients with advanced or metastatic GC receiving ICB. The molecular predictive biomarkers for ICB efficacy were identified to improve the prediction accuracy of ICB efficacy in 22 patients with EBVaGC.ResultsCompared with orthogonal assay (EBER-ISH) results, the NGS-based algorithm achieved high performance with a sensitivity of 95.7% (22/23) and a specificity of 100% (53/53). EBV status was identified as an independent predictive factor for overall survival and progression-free survival in patients with DNA mismatch repair proficient (pMMR) GC following ICB. Moreover, the patients with EBV+/pMMR and EBV−/MMR deficient (dMMR) had comparable and favorable survival following ICB. Twenty-two patients with EBV+/pMMR achieved an objective response rate of 54.5% (12/22) on immunotherapy. Patients with EBVaGC with a high cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) level were less responsive to anti-programmed death-1/ligand 1 (PD-1/L1) monotherapy, and the combination of anti-CTLA-4 plus anti-PD-1/L1 checkpoint blockade benefited patients with EBVaGC more than anti-PD-1/L1 monotherapy with a trend close to significance (p=0.074). There were nearly significant differences in tumor mutational burden (TMB) level and SMARCA4 mutation frequency between the ICB response and non-response group.ConclusionsWe developed an efficient NGS-based EBV detection strategy, and this strategy-identified EBV infection was as effective as dMMR in predicting ICB efficacy in GC. Additionally, we identified CTLA-4, TMB, and SMARCA4 mutation as potential predictive biomarkers of ICB efficacy in EBVaGC, which might better inform ICB treatment for EBVaGC.

regulates renal tubular cell plasticity by activation of Ras and its downstream signaling.