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

Abstract

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.

The Human Ureaplasma Species as Causative Agents of Chorioamnionitis

“…Allam et al reported that U. parvum significantly increased filamin A phosphorylation at serine 2152 in human benign prostate cells and altered its intracellular distribution (240). Filamin A is an actin-binding protein that regulates the cytoskeleton and is involved in antimicrobial signaling pathways (241). Further investigation into the upstream and downstream signaling events may therefore reveal novel insights into Ureaplasma-host interactions.…”

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

“…Mutations in RNase L correlate with HPC and RNase L interacts with AR and Filamin A (FLNA) [3,25]. To determine the role of RNase L in HPC, we first examined the effect of androgen, R1881, on the interaction of RNase L with AR and FLNA.…”

“…Other non-canonical roles of RNase L in regulating barrier function, cellular differentiation, senescence, development of diabetes, lipid storage and demyelination of axons indicate broader roles than the established antiviral functions [3,4,5,6,7]. Genetic association of Hereditary Prostate Cancer 1 ( HPC1 ) to RNASEL expands the role of RNase L to include tumor suppression [8].…”

“…RNase L interacts with several cellular proteins like Filamin A, IQ (isoleucineglutamine) motif containing GTPase activating protein 1 (IQGAP1), ligand of numb protein X (LNX), androgen receptor (AR), extracellular matrix (ECM) and cytoskeletal proteins that may provide alternative mechanisms by which it mediates biological functions [3,23,24,25,26]. Recently, we have shown a nuclease-independent role of RNase L in regulating actin dynamics by interacting with an actin-binding protein, Filamin A, to regulate virus entry [3].…”

“…Recently, we have shown a nuclease-independent role of RNase L in regulating actin dynamics by interacting with an actin-binding protein, Filamin A, to regulate virus entry [3]. RNase L was also reported to interact with AR in breast cancer cells [25].…”