Human NLRP1 is a sensor for double-stranded RNA

  • Science. 2021 Jan 29;371(6528):eabd0811. doi: 10.1126/science.abd0811.
Stefan Bauernfried  1 ,  Matthias J Scherr  2 ,  Andreas Pichlmair  3  4 ,  Karl E Duderstadt  2  5 ,  Veit Hornung  6  2
Affiliations
  • 1. Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 2. Max-Planck Institute of Biochemistry, Martinsried, Germany.
  • 3. Institute of Virology, Technical University of Munich, School of Medicine, Munich, Germany.
  • 4. German Center for Infection Research (DZIF), Munich, Germany.
  • 5. Physics Department, Technical University of Munich, Garching, Germany.
  • 6. Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany. [email protected].
PMID: 33243852 DOI: 10.1126/science.abd0811
Abstract

Inflammasomes function as intracellular sensors of pathogen Infection or cellular perturbation and thereby play a central role in numerous diseases. Given the high abundance of NLRP1 in epithelial barrier tissues, we screened a diverse panel of viruses for inflammasome activation in keratinocytes. We identified Semliki Forest virus (SFV), a positive-strand RNA virus, as a potent activator of human but not murine NLRP1B. SFV replication and the associated formation of double-stranded (ds) RNA was required to engage the NLRP1 inflammasome. Moreover, delivery of long dsRNA was sufficient to trigger activation. Biochemical studies revealed that NLRP1 binds dsRNA through its leucine-rich repeat domain, resulting in its NACHT domain gaining adenosine triphosphatase activity. Altogether, these results establish human NLRP1 as a direct sensor for dsRNA and thus RNA virus Infection.