Abstract
Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V and W proteins which share with P their N-terminal, intrinsically disordered domain (NTD) and possess a unique C-terminal domain. Henipavirus W proteins antagonize interferon (IFN) signaling through NTD-mediated binding to STAT1 and STAT4, and prevent type I IFN expression and production of chemokines. Structural and molecular information on Henipavirus W proteins is lacking. By combining various bioinformatic approaches, we herein show that the Henipaviruses W proteins are predicted to be prevalently disordered and yet to contain short order-prone segments. Using limited proteolysis, differential scanning fluorimetry, analytical size exclusion chromatography, far-UV circular dichroism and small-angle X-ray scattering, we experimentally confirmed their overall disordered nature. In addition, using Congo red and Thioflavin T binding assays and negative-staining transmission electron microscopy, we show that the W proteins phase separate to form amyloid-like fibrils. The present study provides an additional example, among the few reported so far, of a viral protein forming amyloid-like fibrils, therefore significantly contributing to enlarge our currently limited knowledge of viral amyloids. In light of the critical role of the Henipavirus W proteins in evading the host innate immune response and of the functional role of phase separation in biology, these studies provide a conceptual asset to further investigate the functional impact of the phase separation abilities of the W proteins.
Highlights
IntroductionThe Nipah and Hendra viruses (NiV and HeV) are zoonotic pathogens gathered in the Henipavirus genus within the Paramyxoviridae family in the Mononegavirales order
This study reports the characterization of the conformational properties of the Henipavirus W proteins, two key proteins in the host-pathogen race for which molecular data were hitherto conspicuously lacking
The disordered nature of the W proteins likely endows them with several functional advantages such as (i) ability to interact with a large panel of proteins, (ii) increased exposure of post-translational modifications (PTMs) sites, (iii) modulation of interaction strength and accessibility of binding sites through PTMs, (iv) alleviation of structural constraints on overlapping coding regions and mutational robustness, and (v) ability to phase-separate and to form amyloid-like fibrils in the condensed phase
Summary
The Nipah and Hendra viruses (NiV and HeV) are zoonotic pathogens gathered in the Henipavirus genus within the Paramyxoviridae family in the Mononegavirales order. In human beings they cause severe acute respiratory syndrome, generalized vasculitis and lethal encephalitis. Their natural reservoir are fruit-eating bats of the Pteropus genus, the so-called flying foxes [1,2]. HeV came to light in 1994 in the Hendra suburb of Brisbane (Australia) as a new agent responsible for a sudden outbreak of an acute respiratory and neurologic disease within horses [1]. Exposure to body fluids and tissues or excretions of infected horses resulted in transmission to humans, with a high case fatality (~60%)
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