Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells.
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.
Fujian 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.
Jun
J
Wang
Fujian 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.
Yu
Y
Zhang
Fujian 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.
Qiping
Q
Xu
Fujian 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.
Jinhua
J
Qiu
Fujian 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.
Honghua
H
Zheng
Fujian 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.
Xiang
X
Ye
School of Pharmaceutical Sciences at Xiamen University, Xiamen, Fujian 361102, China.
Yuhua
Y
Xue
The Fifth People's Hospital of Wuxi, Affiliated to Jiangnan University, Wuxi, Jiangsu 214005, China.
Yongmei
Y
Yin
State 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.
Zhou
Z
Zhang
State 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.
Ying
Y
Liu
State 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.
Yanling
Y
Hao
Institute of Laboratory Animal Sciences of Chinese Academy of Medical Science, Beijing 100021, China.
Qiang
Q
Wei
Institute of Laboratory Animal Sciences of Chinese Academy of Medical Science, Beijing 100021, China.
Wei
W
Wang
AIDS Research Center, National Institute of Infectious Disease, Tokyo 862-1640, Japan.
Kazuyasu
K
Mori
Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Shuji
S
Izumo
Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Ryuji
R
Kubota
State 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.
Yiming
Y
Shao
Fujian 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.
Hui Qin
HQ
Xing
D015526:AIDS Dementia Complex; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D005455:Fluorescent Antibody Technique; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism* / Q000473:pathology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D054322:tat Gene Products, Human Immunodeficiency Virus
Tat; apoptosis; human immunodeficiency virus-associated neurocognitive disorder; menin; neuron