The cofilin phosphatase slingshot homolog 1 (SSH1) links NOD1 signaling to actin remodeling

PLoS Pathog. 2014 Sep 4;10(9):e1004351. doi: 10.1371/journal.ppat.1004351. eCollection 2014 Sep.

Abstract

NOD1 is an intracellular pathogen recognition receptor that contributes to anti-bacterial innate immune responses, adaptive immunity and tissue homeostasis. NOD1-induced signaling relies on actin remodeling, however, the details of the connection of NOD1 and the actin cytoskeleton remained elusive. Here, we identified in a druggable-genome wide siRNA screen the cofilin phosphatase SSH1 as a specific and essential component of the NOD1 pathway. We show that depletion of SSH1 impaired pathogen induced NOD1 signaling evident from diminished NF-κB activation and cytokine release. Chemical inhibition of actin polymerization using cytochalasin D rescued the loss of SSH1. We further demonstrate that NOD1 directly interacted with SSH1 at F-actin rich sites. Finally, we show that enhanced cofilin activity is intimately linked to NOD1 signaling. Our data thus provide evidence that NOD1 requires the SSH1/cofilin network for signaling and to detect bacterial induced changes in actin dynamics leading to NF-κB activation and innate immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry
  • Actins / metabolism*
  • Blotting, Western
  • Cells, Cultured
  • Cofilin 1 / genetics
  • Cofilin 1 / metabolism*
  • Dysentery, Bacillary / microbiology*
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression Regulation
  • HeLa Cells
  • High-Throughput Screening Assays
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Inflammation
  • Inflammation Mediators / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nod1 Signaling Adaptor Protein / antagonists & inhibitors
  • Nod1 Signaling Adaptor Protein / genetics
  • Nod1 Signaling Adaptor Protein / metabolism*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Shigella flexneri / physiology*
  • Signal Transduction

Substances

  • Actins
  • Cofilin 1
  • Inflammation Mediators
  • NF-kappa B
  • NOD1 protein, human
  • Nod1 Signaling Adaptor Protein
  • RNA, Messenger
  • RNA, Small Interfering
  • Phosphoprotein Phosphatases
  • SSH1 protein, human

Grant support

This work was supported by grants of the DFG (SFB670) and the Koeln Fortune Program/Faculty of Medicine, University of Cologne to TAK and the Heidelberg Academy of Science and Humanities to AH (WIN-Kolleg). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.