The deleterious variants of N-acetylgalactosamine-6-sulfatase (GalN6S) enzyme trigger Morquio a syndrome by disrupting protein foldings.

Lysosomal enzymes degrade cellular macromolecules, while their inactivation causes human hereditary metabolic disorders. Mucopolysaccharidosis IVA (MPS IVA; Moquio A syndrome) is one of the lysosomal storage disorders caused by a defective Galactosamine-6-sulfatase (GalN6S) enzyme. In several populations, disease incidence is elevated due to missense mutations brought on by non-synonymous allelic variation in the GalN6S enzyme. Here, we studied the effect of non-synonymous single nucleotide polymorphism (nsSNPs) on the structural dynamics of the GalN6S enzyme and its binding with N-acetylgalactosamine (GalNAc) using all-atom molecular dynamics simulation and an essential dynamics approach. Consequently, in this study, we have identified three functionally disruptive mutations in domain-I and domain-II, that is, S80L, R90W, and S162F, which presumably contribute to post-translational modifications. The study delineated that both domains work cooperatively, and alteration in domain II (S80L, R90W) leads to conformational changes in the catalytic site in domain-I, while mutation S162F mainly provokes higher residual flexibility of domain II. These results show that these mutations impair the hydrophobic core, implying that Morquio A syndrome is caused by misfolding of the GalN6S enzyme. The results also show the instability of the GalN6S-GalNAc complex upon substitution. Overall, the structural dynamics resulting from point mutations give the molecular rationale for Moquio A syndrome and, more importantly, the Mucopolysaccharidoses (MPS) family of diseases, re-establishing MPS IVA as a protein-folding disease.Communicated by Ramaswamy H. Sarma.

Targeting the mechanism of IRF3 in sepsis-associated acute kidney injury via the Hippo pathway.

Sepsis-induced inflammatory damage and adaptive repair are critical in the pathophysiological mechanisms of acute kidney injury (AKI). Here, we investigated the role of interferon regulatory factor three (IRF3) and subsequent activation of the Hippo pathway in inflammatory damage and repair using an in vitro cell model of LPS-induced AKI. LPS caused the phosphorylation and activation of IRF3 in the early stages of sepsis, and activated IRF3 enhanced the production of type I interferon (IFN), resulting in an excessive inflammatory response. Furthermore, LPS generated considerably more inflammatory injury than intended cell death, and IRF3 activation triggered the Hippo pathway, causing a reduction in YAP, which eventually impaired proliferation and repair in surviving renal tubular epithelial cells and exacerbated the development of AKI. In conclusion, IRF3 promoted the development of sepsis-associated AKI (SAKI) by modulating the Hippo pathway.

Integrated analysis identified NPNT as a potential key regulator in tumor metastasis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the lethal malignancies worldwide. Tumor metastasis is the main cause of HCC related death. Although progress has been made in the mechanism study of HCC in the past decades, the underlying mechanism of HCC metastasis has not been fully illustrated. In the present study, bioinformatic analysis including weighted gene co-expression network analysis (WGCNA), differentially expressed gene analysis, and gene enrichment analysis were applied to discover genes correlated with HCC metastasis. Immunohistochemistry (IHC) assays were applied to detect the expression of NPNT in HCC samples. Cell transfection, wound healing, matrigel transwell assays, and western blot assays were utilized to evaluate the effects of NPNT on cell migration and invasion and signaling pathway variation. We found that NPNT was up-regulated in HCC tumor tissues compared with normal tissues. Especially, NPNT was highly expressed in metastatic tumor compared with non-metastatic HCC tumors. Down-regulation of NPNT via siRNA transfection inhibited cell migration, invasion, and FAK/PI3K/AKT signaling pathway in HCC. Our results demonstrate that NPNT is a potential key regulator in HCC metastasis.

Chemotherapy and chemo-resistance in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) and occurs frequently in the south of China and Southeast Asian countries. Concurrent chemo-radiotherapy is one of the main treatments for NPC. Although, the combined treatment of chemo-radiotherapy produces a satisfying survival rate, the chemo-resistance arises as a big obstacle in curing recurrent NPC patients. The acquirement of chemo-resistance is usually along with a poor prognosis. So far, the mechanism of chemo-resistance in NPC has not been fully elucidated and there have not been a comprehensive review on this issue. Thus, it is of great significance to summarize the mechanisms involved in NPC chemo-resistance. In this review, the importance and limitations of chemotherapy and the mechanisms of chemo-resistances in NPC were discussed.