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The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B

Ryuta Inukai1, Kanako Mori1, Keiko Kuwata2

  • 1Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.

International Journal of Molecular Sciences
|January 28, 2021
PubMed

Insights

Apoptosis-linked gene 2 (ALG-2) promotes cell death by linking the pro-apoptotic protein CDIP1 to the ESCRT-I complex. This interaction, dependent on calcium and specific ESCRT-I subunits, influences cell death sensitivity and potential drug responses.

Area of Science:

  • Molecular and Cellular Biology
  • Cell Death and Apoptosis
  • Protein-Protein Interactions

Background:

  • Apoptosis-linked gene 2 (ALG-2) is a calcium-binding protein implicated in apoptosis, but its precise role remains unclear.
  • Cell death-inducing p53 target protein 1 (CDIP1) is a pro-apoptotic protein whose interactions in cell death pathways require further elucidation.

Purpose of the Study:

  • To investigate the interaction between ALG-2 and CDIP1 in the context of apoptosis.
  • To determine the role of ALG-2 in mediating CDIP1-induced cell death.
  • To explore the involvement of the endosomal sorting complex required for transport-I (ESCRT-I) in this process.

Main Methods:

  • Co-immunoprecipitation assays to analyze protein-protein interactions between ALG-2, CDIP1, and ESCRT-I subunits.
  • Overexpression studies in HEK293 cells to assess the impact of CDIP1, ALG-2, and ESCRT-I on caspase-3/7-mediated cell death.
  • Site-directed mutagenesis of CDIP1's FFAT-like motif to evaluate its role in cell death induction.

Main Results:

  • CDIP1 interacts with ALG-2 in a calcium-dependent manner.
  • ALG-2 acts as an adaptor, facilitating the association of CDIP1 with ESCRT-I, particularly isoforms containing VPS37B or VPS37C.
  • Overexpression of CDIP1 induces caspase-3/7-mediated cell death, which is enhanced by co-expression of ALG-2 and ESCRT-I.
  • CDIP1 binds to VAPA and VAPB via an FFAT-like motif, crucial for CDIP1-induced cell death.

Conclusions:

  • ALG-2 promotes CDIP1-induced apoptosis by enhancing the interaction between CDIP1 and the ESCRT-I complex.
  • The FFAT-like motif in CDIP1 is essential for its pro-apoptotic function and interaction with VAPA/VAPB.
  • Expression levels of ALG-2, ESCRT-I subunits, VAPA, and VAPB may influence sensitivity to CDIP1-associated anticancer drugs.
Keywords:
ESCRT-IPDCD6VAPAVAPBadaptorcalcium-binding proteincell deathprotein-protein interaction

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