RNase L Interacts with Filamin A To Regulate Actin Dynamics and Barrier Function for Viral Entry

The actin cytoskeleton and its network of associated proteins constitute a physical barrier that viruses must circumvent to gain entry into cells for productive infection. The mechanisms by which the physical signals of infection are sensed by the host to activate an innate immune response are not well understood. The antiviral endoribonuclease RNase L is ubiquitously expressed in a latent form and activated upon binding 2-5A, a unique oligoadenylate produced during viral infections. We provide evidence that RNase L in its inactive form interacts with the actin-binding protein Filamin A to modulate the actin cytoskeleton and inhibit virus entry. Cells lacking either RNase L or Filamin A displayed increased virus entry which was exacerbated in cells lacking both proteins. RNase L deletion mutants that reduced Filamin A interaction displayed a compromised ability to restrict virus entry, supporting the idea of an important role for the RNase L-Filamin A complex in barrier function. Remarkably, both the wild type and a catalytically inactive RNase L mutant were competent to reduce virus entry when transfected into RNase L-deficient cells, indicating that this novel function of RNase L is independent of its enzymatic activity. Virus infection and RNase L activation disrupt its association with Filamin A and release RNase L to mediate its canonical nuclease-dependent antiviral activities. The dual functions of RNase L as a constitutive component of the actin cytoskeleton and as an induced mediator of antiviral signaling and effector functions provide insights into its mechanisms of antiviral activity and opportunities for the development of novel antiviral agents

Comparison of angular and linear measurements of soft tissue profile between cephalograms and photograph in subjects with class I and II malocclusion in North Indian population- A comparative study

Aim: The aim of the present study was to compare angular and linear measurements of soft tissue profile between cephalograms and photograph in subjects with Class I and Class II malocclusion. Method: Samples consist of digital lateral cephalograms and profile photograph of 100 subjects (50 Class I and 50 Class II, 25 males and 25 females in each group) between age ranges of 18 to 35 years (mean age 22+/- 2.32). All records were taken in natural head position, centric occlusion and lips in relaxed position. Intra-class correlation coefficients (ICCs) were calculated from repeated photographic measurements to evaluate method reliability. Seven angular and fourteen linear parameters were measured for soft tissue analysis on both lateral cephalogram and photographs. Student’s t-test was done for making adequate comparison. Results: The reliability of the photographic technique was found satisfactory and no statistical difference in angular as well as linear parameters was found for soft tissue profile on both photographs &cephalogramsrespectively. Conclusion: Photographs can be used as an alternative for cephalograms in epidemiologically large-scale studies, where there is a need for cost effective, non-invasive techniques

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene