Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells
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Jun Wang1,*, Yu Zhang1,*, Qiping Xu1,*, Jinhua Qiu1, Honghua Zheng1, Xiang Ye1,*, Yuhua Xue2, Yongmei Yin3, Zhou Zhang4, Ying Liu4, Yanling Hao4, Qiang Wei5, Wei Wang5, Kazuyasu Mori6, Shuji Izumo7, Ryuji Kubota7, Yiming Shao4, Hui Qin Xing1
1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Pathology, Basic Medicine, Medical College, Xiamen University, Xiamen, Fujian 361102, China
2School of Pharmaceutical Sciences at Xiamen University, Xiamen, Fujian 361102, China
3The Fifth People’s Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu 214005, China
4State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
5Institute of Laboratory Animal Sciences of Chinese Academy of Medical Science, Beijing 100021, China
6AIDS Research Center, National Institute of Infectious Disease, Tokyo 862-1640, Japan
7Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
*These authors have contributed equally to this work
Hui Qin Xing, email: firstname.lastname@example.org
Yiming Shao, email: email@example.com
Keywords: menin, Tat, neuron, apoptosis, human immunodeficiency virus-associated neurocognitive disorder
Received: July 26, 2016 Accepted: January 03, 2017 Published: February 02, 2017
The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.
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