title: Glutathione-S-transferase omega 1 (GSTO1-1) acts as mediator of signaling pathways involved in aflatoxin B1-induced apoptosis-autophagy crosstalk in macrophages.
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 (6h) 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 (12h) 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 12h. As a detailed molecular mechanism, we found that the unfolded protein response (UPR) machinery was active at 12h 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.
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Souren
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Rekha
authors.initials: R
authors.lastname: Jakhar
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea.
authors.forename: Monika
authors.initials: M
authors.lastname: Bhardwaj
authors.affiliation: Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook 712-714, Republic of Korea. Electronic address: sckang@daegu.ac.kr.
authors.forename: Sun Chul
authors.initials: SC
authors.lastname: Kang
mesh_terms: D016604:Aflatoxin B1 / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011042:Poisons / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002352:Carrier Proteins; C117709:Gsto1 protein, mouse; D011042:Poisons; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016604:Aflatoxin B1; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: Aflatoxin; Apoptosis; Autophagy; Glutathione-S-transferase; JNK; Protein glutathionylation; Unfolded protein response