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2021 Vol. 12, No. 10

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Chaperone-mediated autophagy is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of neurodegenerative diseases. In this issue, Xu et al. (769–787) presented metformin can induce CMA via activation of TAK1-IKKα/β signaling which leads to phosphorylation of Hsc70. As the cover image showed the activation of this pathway can accelerate the degradation of APP. In the APP/ PS1 mouse model of Alzheimer’s disease, activation of CMA reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. They provide a new evidence that CMA is involved in neurodegenerative diseases and suggest a potential intervention strategy.

Recollection
Professor Haowen Xu: The founder of exercise biochemistry in China
Wei Gong, Yijing Shen, Jiaqi Bao, Yike Ying, Han Zhou, Zhifeng Wu
2021, 12(10): 747-750. doi: 10.1007/s13238-019-00663-z
[Abstract](792) [PDF 637KB](31)
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Highlight
Single cell RNA and immune repertoire profiling of COVID-19 patients reveal novel neutralizing antibody
Fang Li, Meng Luo, Wenyang Zhou, Jinliang Li, Xiyun Jin, Zhaochun Xu, Liran Juan, Zheng Zhang, Yuou Li, Renqiang Liu, Yiqun Li, Chang Xu, Kexin Ma, Huimin Cao, Jingwei Wang, Pingping Wang, Zhigao Bu, Qinghua Jiang
2021, 12(10): 751-755. doi: 10.1007/s13238-020-00807-6
[Abstract](836) [PDF 1673KB](79)
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Review
The exploration of N6-deoxyadenosine methylation in mammalian genomes
Xuwen Li, Zijian Zhang, Xinlong Luo, Jacob Schrier, Andrew D. Yang, Tao P. Wu
2021, 12(10): 756-768. doi: 10.1007/s13238-021-00866-3
[Abstract](723) [PDF 465KB](59)
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N6-methyladenine (N6-mA, m6dA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response. Here, we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes, predominantly mammals.
Research articles
Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model
Xiaoyan Xu, Yaqin Sun, Xufeng Cen, Bing Shan, Qingwei Zhao, Tingxue Xie, Zhe Wang, Tingjun Hou, Yu Xue, Mengmeng Zhang, Di Peng, Qiming Sun, Cong Yi, Ayaz Najafov, Hongguang Xia
2021, 12(10): 769-787. doi: 10.1007/s13238-021-00858-3
[Abstract](1370) [PDF 10478KB](212)
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Chaperone-mediated autophagy (CMA) is a lysosomedependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/ PS1 mouse model of Alzheimer’s disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.
KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma
Shi Wei, Miaomiao Dai, Chi Zhang, Kai Teng, Fengwei Wang, Hongbo Li, Weipeng Sun, Zihao Feng, Tiebang Kang, Xinyuan Guan, Ruihua Xu, Muyan Cai, Dan Xie
2021, 12(10): 788-809. doi: 10.1007/s13238-020-00766-y
[Abstract](1175) [PDF 5707KB](183)
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Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.
Letters
Cooperation-based sperm clusters mediate sperm oviduct entry and fertilization
Yongcun Qu, Qi Chen, Shanshan Guo, Chiyuan Ma, Yonggang Lu, Junchao Shi, Shichao Liu, Tong Zhou, Taichi Noda, Jingjing Qian, Liwen Zhang, Xili Zhu, Xiaohua Lei, Yujing Cao, Wei Li, Nicolas Plachta, Martin M. Matzuk, Masahito Ikawa, Enkui Duan, Ying Zhang, Hongmei Wang
2021, 12(10): 810-817. doi: 10.1007/s13238-021-00825-y
[Abstract](558) [PDF 1720KB](106)
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Molecular deconvolution of the neutralizing antibodies induced by an inactivated SARS-CoV-2 virus vaccine
Xingdong Zhou, Hui Wang, Qun Ji, Mingjuan Du, Yuexia Liang, Huanhuan Li, Fan Li, Hang Shang, Xiujuan Zhu, Wei Wang, Lichun Jiang, Alexey V. Stepanov, Tianyu Ma, Nanxin Gong, Xiaodong Jia, Alexander G. Gabibov, Zhiyong Lou, Yinying Lu, Yu Guo, Hongkai Zhang, Xiaoming Yang
2021, 12(10): 818-823. doi: 10.1007/s13238-021-00840-z
[Abstract](479) [PDF 704KB](64)
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