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1. chinaXiv:201605.01739 [pdf]

Insulin-InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages

Xia, Pengyan; Wang, Shuo; Du, Ying; Huang, Guanling; Fan, Zusen; Huang, Guanling; Satoh, Takashi; Akira, Shizuo
Subjects: Biology >> Biophysics >> Immunology

The lineage commitment of HSCs generates balanced myeloid and lymphoid populations in hematopoiesis. However, the underlying mechanisms that control this process remain largely unknown. Here, we show that insulin-insulin receptor (InsR) signaling is required for lineage commitment of multipotent progenitors (MPPs). Deletion of Insr in murine bone marrow causes skewed differentiation of MPPs to myeloid cells. mTOR acts as a downstream effector that modulates MPP differentiation. mTOR activates Stat3 by phosphorylation at serine 727 under insulin stimulation, which binds to the promoter of Ikaros, leading to its transcription priming. Our findings reveal that the insulin-InsR signaling drives MPP differentiation into lymphoid lineages in early lymphopoiesis, which is essential for maintaining a balanced immune system for an individual organism.

submitted time 2016-05-15 Hits882Downloads441 Comment 0

2. chinaXiv:201605.01431 [pdf]

IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation

Xia, Pengyan; Wang, Shuo; Xiong, Zhen; Ye, Buqing; Fan, Zusen; Xiong, Zhen; Fan, Zusen; Huang, Li-Yu; Han, Ze-Guang; Huang, Li-Yu; Han, Ze-Guang; Huang, Li-Yu; Han, Ze-Guang
Subjects: Biology >> Biophysics

RNA virus infection is recognized by the RIG-I family of receptors that activate the mitochondrial adaptor MAVS, leading to the clearance of viruses. Antiviral signalling activation requires strict modulation to avoid damage to the host from exacerbated inflammation. Insulin receptor tyrosine kinase substrate (IRTKS) participates in actin bundling and insulin signalling and its deficiency causes insulin resistance. However, whether IRTKS is involved in the regulation of innate immunity remains elusive. Here we show that IRTKS deficiency causes enhanced innate immune responses against RNA viruses. IRTKS-mediated suppression of antiviral responses depends on the RIG-I-MAVS signalling pathway. IRTKS recruits the E2 ligase Ubc9 to sumoylate PCBP2 in the nucleus, which causes its cytoplasmic translocation during viral infection. The sumoylated PCBP2 associates with MAVS to initiate its degradation, leading to downregulation of antiviral responses. Thus, IRTKS functions as a negative modulator of excessive inflammation.

submitted time 2016-05-12 Hits702Downloads288 Comment 0

3. chinaXiv:201605.01376 [pdf]

The Endoplasmic Reticulum Adaptor Protein ERAdP Initiates NK Cell Activation via the Ubc13-Mediated NF-kappa B Pathway

Chen, Jun; Hao, Lu; Li, Chong; Ye, Buqing; Du, Ying; Zhang, Honglian; Zhu, Pingping; Liu, Benyu; Yang, Liuliu; Fan, Zusen; Chen, Jun; Hao, Lu; Long, Bo; Long, Bo; Li, Peifeng; Tian, Yong
Subjects: Biology >> Biophysics >> Immunology

NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-kappa B pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-kappa B essential modulator ubiquitination to trigger the Ubc13-mediated NF-kappa B pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.

submitted time 2016-05-12 Hits939Downloads455 Comment 0

4. chinaXiv:201605.01374 [pdf]

Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection

Xia, Pengyan; Wang, Shuo; Ye, Buqing; Du, Ying; Huang, Guanling; Zhu, Pingping; Fan, Zusen
Subjects: Biology >> Biophysics >> Immunology

Neutrophils express Toll-like receptors (TLRs) for the recognition of conserved bacterial elements to initiate antimicrobial responses. However, whether other cytosolic DNA sensors are expressed by neutrophils remains elusive. Here we found constitutive expression of the transcription factor Sox2 in the cytoplasm of mouse and human neutrophils. Neutrophil-specific Sox2 deficiency exacerbated bacterial infection. Sox2 directly recognized microbial DNA through its high-mobility-group (HMG) domain. Upon challenge with bacterial DNA, Sox2 dimerization was needed to activate a complex of the kinase TAK1 and its binding partner TAB2, which led to activation of the transcription factors NE-kappa B and AP-1 in neutrophils. Deficiency in TAK1 or TAB2 impaired Sox2-mediated antibacterial immunity. Overall, we reveal a previously unrecognized role for Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils, which might provide potential therapeutic strategies for the treatment of infectious diseases.

submitted time 2016-05-12 Hits854Downloads425 Comment 0

5. chinaXiv:201605.01338 [pdf]

ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells

Zhu, Pingping; Wang, Yanying; Huang, Guanling; Du, Ying; Zhang, Geng; Yan, Xinlong; Xia, Pengyan; Ye, Buqing; Wang, Shuo; Hao, Lu; Wu, Jiayi; Fan, Zusen; He, Lei; Huang, Guanling; Hao, Lu; Wu, Jiayi; Fan, Zusen
Subjects: Biology >> Biophysics

Liver cancer stem cells (CSCs) have been identified and shown to have self-renewal and differentiation properties; however, the biology of these hepatic CSCs remains largely unknown. Here, we analyzed transcriptome gene expression profiles of liver CSCs and non-CSCs from hepatocellular carcinoma (HCC) cells lines and found that the transcription factor (TF) ZIC2 is highly expressed in liver CSCs. ZIC2 was required for the self-renewal maintenance of liver CSCs, as ZIC2 depletion reduced sphere formation and xenograft tumor growth in mice. We determined that ZIC2 acts upstream of the TF OCT4 and that ZIC2 recruits the nuclear remodeling factor (NURF) complex to the OCT4 promoter, thereby initiating OCT4 activation. In HCC patients, expression levels of the NURF complex were consistent with clinical severity and prognosis. Moreover, ZIC2 and OCT4 levels positively correlated to the clinicopathological stages of HCC patients. Altogether, our results indicate that levels of ZIC2, OCT4, and the NURF complex can be detected and used for diagnosis and prognosis prediction of HCC patients. Moreover, these factors may be potential therapeutic targets for eradicating liver CSCs.

submitted time 2016-05-11 Hits511Downloads314 Comment 0

6. chinaXiv:201605.01337 [pdf]

C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling

Zhu, Pingping; Zhu, Pingping; Wang, Yanying; Du, Ying; Huang, Guanling; Zhang, Geng; Yan, Xinlong; Fan, Zusen; He, Lei
Subjects: Biology >> Biophysics

Liver cancer stem cells (CSCs) harbour self-renewal and differentiation properties, accounting for chemotherapy resistance and recurrence. However, the molecular mechanisms to sustain liver CSCs remain largely unknown. In this study, based on analysis of several hepatocellular carcinoma (HCC) transcriptome datasets and our experimental data, we find that C8orf4 is weakly expressed in HCC tumours and liver CSCs. C8orf4 attenuates the self-renewal capacity of liver CSCs and tumour propagation. We show that NOTCH2 is activated in liver CSCs. C8orf4 is located in the cytoplasm of HCC tumour cells and associates with the NOTCH2 intracellular domain, which impedes the nuclear translocation of N2ICD. C8orf4 deletion causes the nuclear translocation of N2ICD that triggers the NOTCH2 signalling, which sustains the stemness of liver CSCs. Finally, NOTCH2 activation levels are consistent with clinical severity and prognosis of HCC patients. Altogether, C8orf4 negatively regulates the self-renewal of liver CSCs via suppression of NOTCH2 signalling.

submitted time 2016-05-11 Hits521Downloads250 Comment 0

7. chinaXiv:201605.01301 [pdf]

The Long Noncoding RNA IncTCF7 Promotes Self-Renewal of Human Liver Cancer Stem Cells through Activation of Wnt Signaling

Wang, Yanying; Du, Ying; Zhu, Pingping; Huang, Guanling; Yan, Xinlong; Ye, Buqing; Li, Chong; Xia, Pengyan; Zhang, Geng; Fan, Zusen; He, Lei; Huang, Guanling; Fan, Zusen; Luo, Jianjun; Tian, Yong; Chen, Runsheng
Subjects: Biology >> Biophysics

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanisms underlying their self-renewal and maintenance are poorly understood. Here, using transcriptome microarray analysis, we identified a long noncoding RNA (IncRNA) termed IncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, IncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that IncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an IncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that IncRNAs can play in tumor growth and propagation.

submitted time 2016-05-11 Hits628Downloads451 Comment 0

8. chinaXiv:201605.01232 [pdf]

The C228T mutation of TERT promoter frequently occurs in bladder cancer stem cells and contributes to tumorigenesis of bladder cancer

Li, Chong; Yang, Zhao; Du, Ying; He, Luyun; Fan, Zusen; Li, Chong; Wu, Song; Cai, Zhiming; Wang, Haifeng; Wang, Jiansong; Bi, Xingang
Subjects: Biology >> Biophysics >> Oncology

Bladder cancer is one of the most common malignant tumors worldwide. Bladder cancer stem cells (BCSCs) have been isolated recently but have not been defined yet. Here we sorted BCSCs from bladder tumor tissues or normal bladder stem cells (NBBCs) from adjacent normal bladder tissues. We found that the C228T mutation (chr5, 1, 295, 228 C > T) of TERT promoter frequently occurs in BCSCs, but not exist in NBBCs. Importantly, introducing the C228T mutation in NBBCs causes TERT overexpression and transformation of bladder cancer. Restoration of the C228T mutation to T228C in BCSCs can recover the TERT expression to a basal level and abolish tumor formation. Additionally, the C228T mutation of TERT promoter triggers TERT expression leading to increased telomerase activity. TERT expression levels are consistent with clinical severity and prognosis of bladder cancer.

submitted time 2016-05-11 Hits410Downloads246 Comment 0

9. chinaXiv:201605.00745 [pdf]

FoxO1-mediated autophagy is required for NK cell development and innate immunity

Wang, Shuo; Xia, Pengyan; Huang, Guanling; Zhu, Pingping; Liu, Jing; Ye, Buqing; Du, Ying; Fan, Zusen;
Subjects: Biology >> Biophysics

Natural killer (NK) cells exert a crucial role in early immune responses as a major innate effector component. However, the underlying mechanisms of NK cell development remain largely elusive. Here we show that robust autophagy appears in the stage of immature NK cells (iNKs), which is required for NK cell development. Autophagy defects result in damaged mitochondria and accumulation of reactive oxygen species (ROS) that leads to apoptosis of NK cells. Autophagy protects NK cell viability during development through removal of damaged mitochondria and intracellular ROS. Phosphorylated Forkhead box O (FoxO)1 is located to the cytoplasm of iNKs and interacts with Atg7, leading to induction of autophagy. FoxO1 deficiency or an inactive FoxO1(AAA) mutant abrogates autophagy initiation in iNKs and impairs NK cell development and viral clearance. Therefore we conclude that FoxO1-mediated autophagy is required for NK cell development and NK cell-induced innate immunity.

submitted time 2016-05-05 Hits483Downloads285 Comment 0

10. chinaXiv:201605.00717 [pdf]

Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity

Xia, Pengyan; Ye, Buqing; Wang, Shuo; Du, Ying; Xiong, Zhen; Fan, Zusen; Zhu, Xiaoxiao; Xiong, Zhen; Fan, Zusen; Tian, Yong; Tian, Yong;
Subjects: Biology >> Biophysics >> Immunology

Cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA during viral infection and catalyzes synthesis of the dinucleotide cGAMP, which activates the adaptor STING to initiate antiviral responses. Here we found that deficiency in the carboxypeptidase CCP5 or CCP6 led to susceptibility to DNA viruses. CCP5 and CCP6 were required for activation of the transcription factor IRF3 and interferons. Polyglutamylation of cGAS by the enzyme TTLL6 impeded its DNA-binding ability, whereas TTLL4-mediated monoglutamylation of cGAS blocked its synthase activity. Conversely, CCP6 removed the polyglutamylation of cGAS, whereas CCP5 hydrolyzed the monoglutamylation of cGAS, which together led to the activation of cGAS. Therefore, glutamylation and deglutamylation of cGAS tightly modulate immune responses to infection with DNA viruses.

submitted time 2016-05-05 Hits705Downloads296 Comment 0

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