TRIM34 modulates influenza virus-activated programmed cell death by targeting Z-DNA-binding protein 1 for K63-linked polyubiquitination

Z-DNA-binding protein 1 (ZBP1) is an innate sensor of influenza A virus (IAV) that participates in IAV-induced programmed cell death. Nevertheless, little is known about the upstream signaling pathways regulating ZBP1. We found that a member of the tripartite motif (TRIM) family, TRIM34, interacted with ZBP1 to promote its K63-linked polyubiquitination. Using a series of genetic approaches, we provide in vitro and in vivo evidence indicating that IAV triggered cell death and inflammatory responses via dependent on TRIM34/ZBP1 interaction. TRIM34 and ZBP1 expression and interaction protected mice from death during IAV infection owing to reduced inflammatory responses and epithelial damage. Additionally, analysis of clinical samples revealed that TRIM34 associates with ZBP1 and mediates ZBP1 polyubiquitination in vivo. Higher levels of proinflammatory cytokines correlated with higher levels of ZBP1 in IAV-infected patients. Taken together, we conclude that TRIM34 serves as a critical regulator of IAV-induced programmed cell death by mediating the K63-linked polyubiquitination of ZBP1.     

PredRSA: a gradient boosted regression trees approach for predicting protein solvent accessibility

Protein solvent accessibility prediction is a pivotal intermediate step towards modeling protein tertiary structures directly from one-dimensional sequences. It also plays an important part in identifying protein folds and domains. Although some methods have been presented to the protein solvent accessibility prediction in recent years, the performance is far from satisfactory. In this work, we propose PredRSA, a computational method that can accurately predict relative solvent accessible surface area (RSA) of residues by exploring various local and global sequence features which have been observed to be associated with solvent accessibility. Based on these features, a novel and efficient approach, Gradient Boosted Regression Trees (GBRT), is first adopted to predict RSA. Experimental results obtained from 5-fold cross-validation based on the Manesh-215 dataset show that the mean absolute error (MAE) and the Pearson correlation coefficient (PCC) of PredRSA are 9.0 % and 0.75, respectively, which are better than that of the existing methods. Moreover, we evaluate the performance of PredRSA using an independent test set of 68 proteins. Compared with the state-of-the-art approaches (SPINE-X and ASAquick), PredRSA achieves a significant improvement on the prediction quality. Our experimental results show that the Gradient Boosted Regression Trees algorithm and the novel feature combination are quite effective in relative solvent accessibility prediction. The proposed PredRSA method could be useful in assisting the prediction of protein structures by applying the predicted RSA as useful restraints.     

Tent5a modulates muscle fiber formation in adolescent idiopathic scoliosis via maintenance of myogenin expression

ObjectiveParavertebral muscle asymmetry may be involved in the pathogenesis of adolescent idiopathic scoliosis (AIS), and the Tent5a protein was recently identified as a novel active noncanonical poly(A) polymerase. We, therefore, explored the function of the AIS susceptibility gene Tent5a in myoblasts.Materials and methodsRNA‐seq of AIS paravertebral muscle was performed, and the molecular differences in paravertebral muscle were investigated. Twenty‐four AIS susceptibility genes were screened, and differential expression of Tent5a in paravertebral muscles was confirmed with qPCR and Western blot. After the knockdown of Tent5a, the functional effects of Tent5a on C2C12 cell proliferation, migration, and apoptosis were detected by Cell Counting Kit‐8 assay, wound‐healing assay, and TUNEL assay, respectively. Myogenic differentiation markers were tested with immunofluorescence and qPCR in vitro, and muscle fiber formation was compared in vivo.ResultsThe AIS susceptibility gene Tent5a was differentially expressed in AIS paravertebral muscles. Tent5a knockdown inhibited the proliferation and migration of C2C12 cells and inhibited the maturation of type I muscle fibers in vitro and in vivo. Mechanistically, the expression of myogenin was decreased along with the suppression of Tent5a.Conclusions Tent5a plays an important role in the proliferation and migration of myoblasts, and it regulates muscle fiber maturation by maintaining the stability of myogenin. Tent5a may be involved in the pathogenesis of AIS by regulating the formation of muscle fiber type I.