PUMA dependent mitophagy by Abrus agglutinin contributes to apoptosis through ceramide generation

Biochim Biophys Acta Mol Cell Res. 2018 Mar;1865(3):480-495. doi: 10.1016/j.bbamcr.2017.12.002. Epub 2017 Dec 8.


PUMA, a BH3-only pro-apoptotic Bcl2 family protein, is known to translocate from the cytosol into the mitochondria in order to induce apoptosis. Interestingly, the induction of PUMA by p53 plays a critical role in DNA damage-induced apoptosis. In this study, we reported mitophagy inducing potential of PUMA triggered by phytolectin Abrus agglutinin (AGG) in U87MG glioblastoma cells and established AGG-induced ceramide acts as the chief mediator of mitophagy dependent cell death through activation of both mitochondrial ROS as well as ER stress. Importantly, AGG upregulates PUMA expression in U87MG cells with the generation of dysfunctional mitochondria, with gain and loss of function of PUMA is shown to alter mitophagy induction. At the molecular level, our study identified that the LC3 interacting region (LIR) located at the C-terminal end of PUMA interacts with LC3 in order to stimulate mitophagy. In addition, AGG is also found to trigger ubiquitination of PUMA which in turn interacted with p62 for prompting mitophagy suggesting that AGG turns on PUMA-mediated mitophagy in U87MG cells in both p62-dependent as well as in p62-independent manner. Interestingly, AGG-triggered ceramide production through activation of ceramide synthase-1 leads to induction of ER stress and ROS accumulation to promote mitochondrial damage as well as mitophagy. Further, upon pre-treatment with Mdivi-1, DRP1 inhibitor, AGG exposure results in suppression of apoptosis in U87MG cells indicating AGG-induced mitophagy switches to apoptosis that can be exploited for better cancer therapeutics.

Keywords: Abrus agglutinin; Apoptosis; Ceramide; LC3 interacting region; Mitophagy; PUMA; Ubiquitin; p62.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics*
  • Ceramides / biosynthesis
  • Ceramides / genetics
  • Cytosol / metabolism
  • DNA Damage / genetics
  • HeLa Cells
  • Humans
  • Mitochondria / genetics
  • Mitophagy / genetics*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Plant Lectins / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-myc / genetics*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction


  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • BCL2 protein, human
  • Ceramides
  • Plant Lectins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Reactive Oxygen Species
  • abrus agglutinin