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CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity

Xin-Ming Jia1, Bing Tang2, Le-Le Zhu3

  • 1Research Center for Translational Medicine, Shanghai East Hospital, and Department of Immunology, Tongji University School of Medicine, Shanghai 200120, China jiaxm@tongji.edu.cn xllin@mdanderson.org.

The Journal of Experimental Medicine
|October 1, 2014
PubMed

Insights

This study reveals a new role for CARD9 in fungal immunity. CARD9 links Dectin-1 signaling to H-Ras and ERK activation, crucial for innate immune responses against Candida albicans.

Area of Science:

  • Immunology
  • Cellular Biology
  • Microbiology

Background:

  • Dectin-1 is a key pattern recognition receptor for fungal infections.
  • Dectin-1 signaling typically involves CARD9-mediated NF-κB activation for innate immunity.

Purpose of the Study:

  • To elucidate the precise role of CARD9 in Dectin-1-induced immune responses.
  • To investigate the molecular mechanism linking Dectin-1 to downstream signaling pathways.

Main Methods:

  • Utilized Dectin-1 ligands (curdlan, Candida albicans yeast) to stimulate immune cells.
  • Investigated protein-protein interactions and signaling pathways involving CARD9, H-Ras, Ras-GRF1, Syk, and ERK.
  • Assessed the impact of ERK inhibition on host survival in a murine fungal infection model.

Main Results:

  • CARD9 is dispensable for Dectin-1-induced NF-κB activation.
  • CARD9 mediates Dectin-1-induced H-Ras and ERK activation via Ras-GRF1.
  • Syk-dependent phosphorylation of Ras-GRF1 by Dectin-1 engagement is essential for CARD9-H-Ras complex formation and ERK activation.
  • Inhibition of ERK signaling exacerbates C. albicans-induced mortality in a CARD9-dependent manner.

Conclusions:

  • Dectin-1 signaling activates ERK through a CARD9-H-Ras-Ras-GRF1 axis, independent of NF-κB.
  • This pathway is critical for innate immune responses and host defense against fungal pathogens like C. albicans.

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