Glutathione-S-transferase omega 1 (GSTO1-1) acts as mediator of signaling pathways involved in aflatoxin B1-induced apoptosis-autophagy crosstalk in macrophages

Souren Paul, Rekha Jakhar, Monika Bhardwaj, Sun Chul Kang

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Aflatoxin B1 (AFB1) is the most toxic aflatoxin species and has been shown to be associated with specific as well as non-specific immune responses. In the present study, using murine macrophage Raw 264.7 cells as a model, we report that short exposure (6 h) to AFB1 caused an increase in the cellular calcium pool in mitochondria, which in turn elevated reactive oxygen species (ROS)-mediated oxidative stress and led to loss of mitochondrial membrane potential and ultimately c-Jun N-terminal kinases (JNK)-mediated caspase-dependent cell death. On the contrary, longer exposure (12 h) to AFB1 reduced JNK phosphorylation and cell death in macrophages. Measurement of autophagic flux demonstrated that autophagy induction through the canonical pathway was responsible for suppressing AFB1-induced apoptosis after 12 h. As a detailed molecular mechanism, we found that the unfolded protein response (UPR) machinery was active at 12 h post-exposure to AFB1 and induced cytoprotective autophagy as confirmed by determination of major autophagic markers. Inhibition of autophagy by Beclin-1 siRNA also resulted in JNK-mediated cell death. We further established that glutathione S transferase omega1-1 (GSTO1-1), a specific class of GST, was the responsible factor between apoptosis and autophagy crosstalk. Targeting of GSTO1-1 increased JNK-mediated apoptosis by 2-fold compared to the control, whereas autophagy rate was reduced. Thus, increased expression of GSTO1-1 was associated with increased protein glutathionylation, an important protein modification in response to cellular redox status.

Original languageEnglish (US)
Pages (from-to)1218-1230
Number of pages13
JournalFree Radical Biology and Medicine
Volume89
DOIs
StatePublished - Dec 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

Keywords

  • Aflatoxin
  • Apoptosis
  • Autophagy
  • Glutathione-S-transferase
  • JNK
  • Protein glutathionylation
  • Unfolded protein response

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