TY - JOUR
T1 - Glutathione-S-transferase omega 1 (GSTO1-1) acts as mediator of signaling pathways involved in aflatoxin B1-induced apoptosis-autophagy crosstalk in macrophages
AU - Paul, Souren
AU - Jakhar, Rekha
AU - Bhardwaj, Monika
AU - Kang, Sun Chul
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/12
Y1 - 2015/12
N2 - 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.
AB - 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.
KW - Aflatoxin
KW - Apoptosis
KW - Autophagy
KW - Glutathione-S-transferase
KW - JNK
KW - Protein glutathionylation
KW - Unfolded protein response
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U2 - 10.1016/j.freeradbiomed.2015.11.006
DO - 10.1016/j.freeradbiomed.2015.11.006
M3 - Article
C2 - 26561775
AN - SCOPUS:84947250687
SN - 0891-5849
VL - 89
SP - 1218
EP - 1230
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -