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Eiger-induced cell death relies on Rac1-dependent endocytosis

W Ruan1, A Srinivasan1, S Lin1

  • 1Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Cell Death & Disease
|April 8, 2016
PubMed

Insights

Tumor necrosis factor receptor (TNFR) superfamily signaling controls cell death. This study reveals Rac1 GTPase and endosomal trafficking are crucial for Eiger-induced JNK activation and cell death in Drosophila.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Developmental biology

Background:

  • Tumor necrosis factor receptor (TNFR) superfamily members regulate cell fate.
  • p75 neurotrophin receptor (p75NTR) signaling activates c-Jun N-terminal kinases (JNKs) to induce cell death.
  • Receptor-proximal signaling events remain unclear.

Purpose of the Study:

  • Identify conserved signaling events in Eiger (Egr)-induced JNK activation and cell death.
  • Elucidate the role of Rac1 GTPase in Egr-mediated cell death.
  • Characterize upstream regulators and downstream effectors of Rac1 in this pathway.

Main Methods:

  • Utilized Drosophila as a model system to study Egr-induced cell death.
  • Investigated the function of Rac1 using loss-of-function and overexpression approaches.
  • Identified Guanine nucleotide Exchange Factor (GEF) for Rac1 and negative regulators.
  • Analyzed the role of endosomal trafficking proteins (Rab21, Rab7) in the pathway.

Main Results:

  • Rac1 GTPase is essential for Egr-induced JNK activation and cell death.
  • Vav acts as a GEF for Rac1, while dLRRK negatively regulates Rac1.
  • Rac1-dependent endosomal entry of Egr is required for JNK activation and cell death.
  • Rab21 and Rab7 are critical for Egr entry into early endosomes.

Conclusions:

  • Rac1 GTPase is a key mediator of Egr-induced cell death.
  • Endosomal trafficking, regulated by Rab proteins, is a critical step for JNK pathway activation.
  • This study reveals novel regulatory mechanisms of Rac1 in cell death signaling.

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