PRKAA/AMPK restricts HBV replication through promotion of autophagic degradation.
Adenosine monophosphate-activated protein kinase (AMPK) is a crucial energy sensor that maintains cellular energy homeostasis. AMPK plays a critical role in macroautophagy/autophagy, and autophagy facilitates hepatitis B virus (HBV) replication. To date, the intrinsic link among AMPK, autophagy and HBV production remains to be elucidated. Here, we demonstrate that PRKAA (a catalytic subunit of AMPK) is activated in response to HBV-induced oxidative stress, which in turn decreases the production of HBV. Mechanistic studies reveal that the autophagy machinery is associated with the inhibitory effect of PRKAA/AMPK on HBV production. Activation of PRKAA/AMPK promotes autolysosome-dependent degradation through stimulation of cellular ATP levels, which then leads to the depletion of autophagic vacuoles. Taken together, our data suggest that the activation of AMPK might be a stress response of host cells to restrict virus production through promotion of autophagic degradation. These findings therefore indicate that AMPK could provide a potential therapeutic target for HBV infection.
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Na
N
Xie
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Kefei
K
Yuan
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.|b Department of Neurology , the Affiliated Hospital of Hainan Medical College , Haikou , China.
Li
L
Zhou
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Kui
K
Wang
c Department of General Surgery , West China Hospital, Sichuan University , Chengdu , China.
Hai-Ning
HN
Chen
d Department of Biochemistry and Molecular Biology , and Molecular Medicine and Cancer Research Center, Chongqing Medical University , Chongqing , China.
Yunlong
Y
Lei
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Jiang
J
Lan
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Qinqin
Q
Pu
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Wei
W
Gao
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Lu
L
Zhang
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Guobo
G
Shen
b Department of Neurology , the Affiliated Hospital of Hainan Medical College , Haikou , China.
Qifu
Q
Li
e Lab for Aging Research, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
Hengyi
H
Xiao
f Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu , Sichuan , China.
Hong
H
Tang
g School of Medicine, Nankai University , Tianjin , China.
Rong
R
Xiang
h Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong , Hong Kong , China.
Mingliang
M
He
i Department of Molecular Microbiology and Immunology , Norris Comprehensive Cancer Center, University of Southern California , Los Angeles , CA , USA.
Pinghui
P
Feng
j Department of Biochemistry and Molecular Biology , Monash University , Clayton , Victoria , Australia.
Edouard C
EC
Nice
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Yuquan
Y
Wei
b Department of Neurology , the Affiliated Hospital of Hainan Medical College , Haikou , China.
Haiyuan
H
Zhang
k Department of Liver Surgery , West China Hospital, Sichuan University , Chengdu , China.
Jiayin
J
Yang
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China.
Canhua
C
Huang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D004261:DNA Replication; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D018384:Oxidative Stress; D010588:Phagosomes / Q000378:metabolism* / Q000821:virology; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism; D014779:Virus Replication
D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human
adenosine monophosphate-activated protein kinase; adenosine triphosphate; autophagy; hepatitis B virus; oxidative stress