Toxoplasma gondii induces autophagy and apoptosis in human umbilical cord mesenchymal stem cells via downregulation of Mcl-1.

Abstract

Autophagy and apoptosis are critical for controlling Toxoplasma gondii (T. gondii) infection. T. gondii infection during pregnancy can damage the fetus and cause birth defects; however, the molecular mechanisms of this process are poorly understood. This study aims to determine the activities of autophagy and apoptosis as well as their regulatory mechanisms during T. gondii infection by using human umbilical cord mesenchymal stem cells (hUC-MSCs) as a model of congenital diseases. LC3B, a hallmark protein of autophagy was incrementally upregulated with the infection duration, whereas p62 was downregulated in T. gondii-infected hUC-MSCs. Concurrent to this result, the invasion of T. gondii into hUC-MSCs increased in a time-dependent manner. The expression levels of Bcl-2 family proteins including Bcl-2, Bcl-xL, Bim, Bax, Bid and Bak were not altered; however, Mcl-1 levels in hUC-MSCs were dramatically decreased upon T. gondii infection. In addition, at 24 h post-infection, cleaved PARP and cleaved caspase-3 protein levels were elevated in hUC-MSCs. Importantly, Mcl-1 overexpression reduced the levels of autophagy- and apoptosis-related proteins in T. gondii-infected hUC-MSCs. Mcl-1 proteins were primarily expressed in the fraction containing mitochondria and strongly interacted with Beclin-1 under normal conditions; however, these interactions were remarkably attenuated by T. gondii infection. These results suggest that mitochondrial Mcl-1 is an essential signaling mediator regulating the activation of autophagy and apoptosis during T. gondii infection.

• Authors: Jia-Qi Chu, Kai-Peng Jing, Xiang Gao, Peng Li, Rui Huang, Yan-Ru Niu, Shou-Quan Yan, Jun-Chao Kong, Cai-Yuan Yu, Ge Shi, Yi-Ming Fan, Young-Ha Lee, Yu Zhou, Juan-Hua Quan
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 16 Issue 5 Pg. 477-486 (Mar 04 2017) ISSN: 1551-4005 [Electronic] United States
• PMID: 28112581 (Publication Type: Journal Article)

Chemical References

• BECN1 protein, human
• Beclin-1
• Myeloid Cell Leukemia Sequence 1 Protein
• TOR Serine-Threonine Kinases

Topics

• Apoptosis
• Autophagy
• Beclin-1
• Cell Survival
• Down-Regulation
• Humans
• Mesenchymal Stem Cells (cytology, metabolism)
• Mitochondria (metabolism)
• Models, Biological
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Protein Binding
• TOR Serine-Threonine Kinases (metabolism)
• Toxoplasma (physiology)
• Umbilical Cord (cytology)