Structural basis for the prion-like MAVS filaments in antiviral innate immunity

Hui Xu, Xiaojing He, Hui Zheng, Lily J. Huang, Fajian Hou, Zhiheng Yu, Michael J ason de la Cruz, Brian Borkowski, Xuewu Zhang, Zhijian J. Chen, Qiu Xing Jiang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)e01489
JournaleLife
Volume3
DOIs
StatePublished - 2014

Fingerprint

Prions
Innate Immunity
Antiviral Agents
Viruses
Caspases
Chemical activation
Mitochondria
RNA Viruses
Coulomb interactions
Static Electricity
Hydrophobic and Hydrophilic Interactions
Point Mutation
Proline
Polymerization
RNA
Electrons
Imaging techniques

Keywords

  • cryoEM reconstruction
  • innate immunity
  • MAVS
  • prion-like filaments
  • three-stranded filaments

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Xu, H., He, X., Zheng, H., Huang, L. J., Hou, F., Yu, Z., ... Jiang, Q. X. (2014). Structural basis for the prion-like MAVS filaments in antiviral innate immunity. eLife, 3, e01489. https://doi.org/10.7554/eLife.01489

Structural basis for the prion-like MAVS filaments in antiviral innate immunity. / Xu, Hui; He, Xiaojing; Zheng, Hui; Huang, Lily J.; Hou, Fajian; Yu, Zhiheng; de la Cruz, Michael J ason; Borkowski, Brian; Zhang, Xuewu; Chen, Zhijian J.; Jiang, Qiu Xing.

In: eLife, Vol. 3, 2014, p. e01489.

Research output: Contribution to journalArticle

Xu, H, He, X, Zheng, H, Huang, LJ, Hou, F, Yu, Z, de la Cruz, MJA, Borkowski, B, Zhang, X, Chen, ZJ & Jiang, QX 2014, 'Structural basis for the prion-like MAVS filaments in antiviral innate immunity', eLife, vol. 3, pp. e01489. https://doi.org/10.7554/eLife.01489
Xu, Hui ; He, Xiaojing ; Zheng, Hui ; Huang, Lily J. ; Hou, Fajian ; Yu, Zhiheng ; de la Cruz, Michael J ason ; Borkowski, Brian ; Zhang, Xuewu ; Chen, Zhijian J. ; Jiang, Qiu Xing. / Structural basis for the prion-like MAVS filaments in antiviral innate immunity. In: eLife. 2014 ; Vol. 3. pp. e01489.
@article{4db3505bd1c34e2f8cf686562b4b919c,
title = "Structural basis for the prion-like MAVS filaments in antiviral innate immunity",
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.",
keywords = "cryoEM reconstruction, innate immunity, MAVS, prion-like filaments, three-stranded filaments",
author = "Hui Xu and Xiaojing He and Hui Zheng and Huang, {Lily J.} and Fajian Hou and Zhiheng Yu and {de la Cruz}, {Michael J ason} and Brian Borkowski and Xuewu Zhang and Chen, {Zhijian J.} and Jiang, {Qiu Xing}",
year = "2014",
doi = "10.7554/eLife.01489",
language = "English (US)",
volume = "3",
pages = "e01489",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Structural basis for the prion-like MAVS filaments in antiviral innate immunity

AU - Xu, Hui

AU - He, Xiaojing

AU - Zheng, Hui

AU - Huang, Lily J.

AU - Hou, Fajian

AU - Yu, Zhiheng

AU - de la Cruz, Michael J ason

AU - Borkowski, Brian

AU - Zhang, Xuewu

AU - Chen, Zhijian J.

AU - Jiang, Qiu Xing

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - cryoEM reconstruction

KW - innate immunity

KW - MAVS

KW - prion-like filaments

KW - three-stranded filaments

UR - http://www.scopus.com/inward/record.url?scp=84964699025&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964699025&partnerID=8YFLogxK

U2 - 10.7554/eLife.01489

DO - 10.7554/eLife.01489

M3 - Article

C2 - 24569476

VL - 3

SP - e01489

JO - eLife

JF - eLife

SN - 2050-084X

ER -