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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 Hits2447Downloads1225 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 Hits1624Downloads827 Comment 0

3. 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 Hits2133Downloads1191 Comment 0

4. 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 Hits2170Downloads1154 Comment 0

5. chinaXiv:201605.00759 [pdf]

Difference of language cortex reorganization between cerebral arteriovenous malformations, cavernous malformations, and gliomas: a functional MRI study

Deng, Xiaofeng; Xu, Long; Zhang, Yan; Wang, Shuo; Zhao, Yuanli; Cao, Yong; Zhang, Dong; Wang, Rong; Ye, Xun; Wu, Jun; Zhao, Jizong; Deng, Xiaofeng; Xu, Long; Zhang, Yan; Wang, Shuo; Zhao, Yuanli; Cao, Yong; Zhang, Dong; Wang, Rong; Ye, Xun
Subjects: Biology >> Biophysics

The authors attempted to demonstrate the difference in language cortex reorganization between cerebral malformations (AVMs), cavernous malformations (CMs), and gliomas by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Clinical and imaging data of 27 AVM patients (AVM-L group), 29 CM patients (CM-L group), and 20 glioma patients (Glioma-L group) were retrospectively reviewed, with lesions overlying the left inferior frontal gyrus (Broca area). As a control, patients with lesions involving the right inferior frontal gyrus were also enrolled, including 14 AVM patients (AVM-R group), 20 CM patients (CM-R group), and 14 glioma patients (Glioma-R group). All patients were right-handed. Lateralization indices (LI) of BOLD signal activations were calculated separately for Broca and Wernicke areas. In AVM-L group, right-sided lateralization of BOLD signals was observed in 10 patients (37.0 %), including 6 in the Broca area alone, 1 in the Wernicke area alone, and 3 in both areas. Three patients (10.3 %) of CM-L group showed right-sided lateralization in both Broca and Wernicke areas, and 1 patient (5.0 %) of Glioma-L group had right-sided lateralization in the Wernicke area alone. A significant difference of right-sided lateralization was observed between the AVM-L group and CM-L group (P = 0.018) and also between the AVM-L group and Glioma-L group (P = 0.027). No patient in AVM-R, CM-R, or Glioma-R groups showed right-sided lateralization. Language cortex reorganization may occur in AVM, CM, and glioma patients when the traditional language cortex was involved by lesions, but the potential of reorganization for CM and glioma patients seems to be insufficient compared with AVM patients.

submitted time 2016-05-05 Hits1331Downloads776 Comment 0

6. 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 Hits1540Downloads845 Comment 0

7. 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 Hits1894Downloads982 Comment 0

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