Abstract
Mitochondrial antiviral signaling (MAVS) protein is required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling cascades, but the underlying structural mechanism is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N-terminal caspase activation and recruitment domain (CARD) of MAVS and a truncated MAVS lacking part of the proline-rich region and the C-terminal transmembrane domain. Both structures are left-handed three-stranded helical filaments, revealing specific interfaces between individual CARD subunits that are dictated by electrostatic interactions between neighboring strands and hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments. DOI: http://dx.doi.org/10.7554/eLife.01489.001.
Highlights
Viral infection of host cells triggers innate and adaptive immune responses that are essential for the survival of the host (Iwasaki and Medzhitov, 2010; Ronald and Beutler, 2010; Takeuchi and Akira, 2010)
Our previous electron microscopic (EM) images of negatively stained specimens suggested that the mitochondrial antiviral signaling protein (MAVS) caspase activation and recruitment domain (CARD) assembles into a filament-like structure in vitro (Hou et al, 2011)
To further uncover the molecular mechanism governing the MAVS CARD self-association, we utilized cryo-electron microscopy (cryoEM) to determine the molecular structure of the CARD filament
Summary
Viral infection of host cells triggers innate and adaptive immune responses that are essential for the survival of the host (Iwasaki and Medzhitov, 2010; Ronald and Beutler, 2010; Takeuchi and Akira, 2010). Initiation of innate immune response relies on a group of pattern recognition receptors, which recognize specific pathogen-associated molecular patterns (PAMPs), including microbial nucleic acids, bacterial cell wall components and certain highly conserved proteins. The second group of sensors resides in the cytosol They belong to a family of cytosolic RNA helicases called RIG-I-like receptors (RLRs), including retinoic acid inducible gene-I (RIG-I), melanoma differentiation-association gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) (Yoneyama and Fujita, 2009). Recognition of viral RNAs by RLRs leads to the activation of mitochondrial antiviral signaling protein (MAVS; known as IPS1, VISA and CARDIF).
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