Regulation of alternative splicing is carried out by RNA-binding proteins. Each alternative splicing event is controlled by several RNA-binding proteins, which in combination create the distribution of alternative splicing products in a given cell type. Transmembrane protein CD44 plays an important role at various stages of the metastatic cascade and is considered as a promising molecule for the therapy of tumor diseases and the construction of prognostic classifiers. However, the functions of specific isoforms of this protein may differ significantly. In this work, we performed a bioinformatic search of RNA-binding proteins that can determine the expression of clinically significant isoforms 3 and 4 of CD44 protein. The analysis revealed five RNA-binding proteins, three of which (OAS1, ZFP36L2, and DHX58) are shown for the first time as potential regulators of the studied process.

Hepatitis C remains a major public health problem in the world. The host immune system plays a key role in viral clearance. This study aimed to investigate the connection between retinoic acid-inducible gene I-like (RIG-I-like) receptor gene polymorphism and hepatitis C chronicity in the Chinese Han population. The current study genotyped three SNPs (IFIH1 rs10930046 and DHX58 rs2074158, rs2074160) to assess their association with the chronicity of hepatitis C virus (HCV) infection among 1,590 participants (590 spontaneous HCV clearance cases and 1,000 persistent infection patients). Our research shows that DHX58 rs2074158-G allele (dominant model: adjusted OR = 1.53, 95% CI [1.20-1.95], P = 0.001; additive model: adjusted OR = 1.50, 95% CI [1.27-1.78], P < 0.001) and IFIH1 rs10930046-C allele (additive model: adjusted OR = 1.26, 95% CI [1.07-1.49], P = 0.005) were associated with chronic hepatitis C (CHC). And the risk of CHC increased in people carrying more unfavorable genotypes (rs2074158-AG/GG or rs10930046-CC), with the chronic rates for genotypes number from zero to two in 60.69%, 57.33%, and 85.93%, respectively (adjusted OR = 3.64, 95% CI [2.18-6.08]; P < 0.001). Genetic polymorphism of IFIH1 and DHX58 may be related to CHC in the Chinese Han population. Furthermore, the risk of CHC increases as the number of unfavorable genotypes carried by the HCV-infected person increases. IFIH1 rs10930046, DHX58 rs2074158, age, ALT, and AST levels were all independent predictors of CHC.

Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), sense viral RNA to induce the antiviral interferon (IFN) response. LGP2, unable to activate the IFN response itself, modulates RIG-I and MDA5 signalling. HDV, a small RNA virus causing the most severe form of viral hepatitis, is sensed by MDA5. The mechanism underlying IFN induction and its effect on HDV replication is unclear. Here, we aimed to unveil the role of LGP2 and clinically relevant variants thereof in these processes.
RLRs were depleted in HDV susceptible HepaRGNTCP cells and primary human hepatocytes. Cells were reconstituted to express different LGP2 versions. HDV and IFN markers were quantified in a time-resolved manner. Interaction studies among LGP2, MDA5, and RNA were performed by pull-down assays.
LGP2 is essential for the MDA5-mediated IFN response induced upon HDV infection. This induction requires both RNA binding and ATPase activities of LGP2. The IFN response only moderately reduced HDV replication in resting cells but profoundly suppressed cell division-mediated HDV spread. An LGP2 variant (Q425R), predominating in Africans who develop less severe chronic hepatitis D, mediated detectably higher basal and faster HDV-induced IFN response as well as stronger HDV suppression. Mechanistically, LGP2 RNA binding was a prerequisite for the formation of stable MDA5-RNA complexes. MDA5 binding to RNA was enhanced by the Q425R LGP2 variant.
LGP2 is essential to mount an antiviral IFN response induced by HDV and stabilises MDA5-RNA interaction required for downstream signalling. The natural Q425R LGP2 is a gain-of-function variant and might contribute to an attenuated course of hepatitis D.
HDV is the causative pathogen of chronic hepatitis D, a severe form of viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Upon infection, the human immune system senses HDV and mounts an antiviral interferon (IFN) response. Here, we demonstrate that the immune sensor LGP2 cooperates with MDA5 to mount an IFN response that represses HDV replication. We mapped LGP2 determinants required for IFN system activation and characterised several natural genetic variants of LGP2. One of them reported to predominate in sub-Saharan Africans can accelerate HDV-induced IFN responses, arguing that genetic determinants, possibly including LGP2, might contribute to slower disease progression in this population. Our results will hopefully prompt further studies on genetic variations in LGP2 and other components of the innate immune sensing system, including assessments of their possible impact on the course of viral infection.

Lysine 63-linked polyubiquitin (K63-Ub) chains activate a range of cellular immune and inflammatory signaling pathways, including the mammalian antiviral response. Interferon and antiviral genes are triggered by TRAF family ubiquitin ligases that form K63-Ub chains. LGP2 is a feedback inhibitor of TRAF-mediated K63-Ub that can interfere with diverse immune signaling pathways. Our results demonstrate that LGP2 inhibits K63-Ub by association with and sequestration of the K63-Ub-conjugating enzyme, Ubc13/UBE2N. The LGP2 helicase subdomain, Hel2i, mediates protein interaction that engages and inhibits Ubc13/UBE2N, affecting control over a range of K63-Ub ligase proteins, including TRAF6, TRIM25, and RNF125, all of which are inactivated by LGP2. These findings establish a unifying mechanism for LGP2-mediated negative regulation that can modulate a variety of K63-Ub signaling pathways.

Discovering genes with regulatory effect of osteoblast differentiation and revealing mechanism of osteogenesis will enable us to find out more therapeutic methods for treating bone diseases. In this study, we supposed DHX58 may have a close relationship with osteogenesis and we then detected the expression of DHX58 during osteogenesis. We found that DHX58 was increased along with the osteogenic induction time extended. We then analyzed the function of DHX58 on ossification of mouse osteoblasts. The knockdown of DHX58 suppressed osteogenesis, as well as the expression of osteogenic biomarkers Runx2, OCN and Col1α1. Besides, the canonical Wnt/β-Catenin signaling pathway was found significant inhibited as DHX58 downregulated, indicating it\'s the downstream pathway of DHX58 in regulating osteogenesis. Furthermore, we overexpressed DHX58 and the results were in accordance with the above findings. Taken together, our results indicated that DHX58 promotes osteogenesis of mouse osteoblasts via the canonical Wnt/β-Catenin signaling pathway.

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.