CDC42 is a member of Rho GTPase family that regulates various biological processes and its activity can be hijacked by invading pathogens. Here, we discovered that the level of active CDC42 in hepatocytes positively correlates with the entry capacity of hepatitis B virus (HBV). Mechanistically, CDC42 activation effectively promotes the transport of the viral receptor sodium taurocholate co-transporting polypeptide (NTCP) to the plasma membrane via Rab11 dependent recycling endosomal pathway. NTCP interacts with Rab11 and activation of CDC42 signaling reinforces the interaction between NTCP and Rab11. We further show that clathrin mediated endocytosis (CME), the known HBV entry pathway, is independent of CDC42 activity. Intriguingly, we reveal that CDC42 dependent macropinocytosis is a route for HBV entry, which is equally essential for viral infection as CME. Together, our findings uncover new mechanisms for HBV entry that involve unrecognized functions of CDC42 and suggest that Rho GTPase signaling might represent a potential target for antiviral therapy.
Lin-Lin Hu,Hong-Ge Li,Xiao-Mei Li,Yi Xu,Ya-Qin Pang,Bin Wang,Jun-Li Wang,Shao-Chen Sun
Nonylphenol (NP) belongs to the metabolites of commercial detergents, which acts as an environmental endocrine disruptor . NP is reported to have multiple toxicity including reproductive toxicity. In present study, we reported the protective effects of melatonin on the NP-exposed oocyte quality. We set up a mouse in vivo model of NP exposure (500 μg/L), by daily drinking and continued feeding for 4 weeks; and we gave a daily dose of melatonin (30 mg/kg) to the NP-exposed mice. Melatonin supplementation restores the development ability of oocytes exposed to NP, and this was due to the reduction of ROS level and DNA damage by melatonin. Melatonin could rescue aberrant mitochondria distribution, mitochondria membrane potential, which also was reflected by ATP content and mtDNA copy number. Moreover, melatonin could restore the RPS3 expression to ensure the ribosome function for protein synthesis , and reduced GRP78 protein level to protect against ER stress and ER distribution defects. We also found that vesicle protein Rab11 from Golgi apparatus was protected by melatonin at the spindle periphery of oocytes of NP-exposed mice, which further moderated LAMP2 for lysosome function. Our results indicate that melatonin protects oocytes from NP exposure through its effects on the reduction of oxidative stress and DNA damage, which might be through its amelioration on the organelles in mice.
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