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1. chinaXiv:201605.01731 [pdf]

GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3

Zhang, Dongdong; Zhang, Weimin; Li, Dan; Fu, Ming; Zhan, Qimin; Zhang, Dongdong; Zhang, Weimin; Li, Dan; Fu, Ming; Zhan, Qimin; Zhang, Dongdong; Chen, Runsheng; Zhan, Qimin
Subjects: Biology >> Biophysics >> Cell Biology

GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A(1) treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation.

submitted time 2016-05-15 Hits1690Downloads988 Comment 0

2. chinaXiv:201605.01517 [pdf]

Ribosylation triggering Alzheimer's disease-like Tau hyperphosphorylation via activation of CaMKII

Wei, Yan; Han, Chanshuai; Wang, Yujing; Wu, Beibei; Su, Tao; Liu, Ying; He, Rongqiao; Wang, Yujing; Wu, Beibei; Liu, Ying; He, Rongqiao
Subjects: Biology >> Biophysics >> Cell Biology

Type 2 diabetes mellitus (T2DM) is regarded as one of the serious risk factors for age-related cognitive impairment; however, a causal link between these two diseases has so far not been established. It was recently discovered that, apart from high D-glucose levels, T2DM patients also display abnormally high concentrations of uric D-ribose. Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells. However, the administration of D-glucose showed no significant changes in Tau phosphorylation under the same experimental conditions. Crucially, suppression of AGE formation using an AGEs inhibitor (aminoguanidine) effectively prevents hyperphosphorylation of Tau protein. Further study shows AGEs resulted from ribosylation activate calcium-/calmodulin-dependent protein kinase type II (CaMKII), a key kinase responsible for Tau hyperphosphorylation. These data suggest that there is indeed a mechanistic link between ribosylation and Tau hyperphosphorylation. Targeting ribosylation by inhibiting AGE formation may be a promising therapeutic strategy to prevent Alzheimer's disease-like Tau hyperphosphorylation and diabetic encephalopathies.

submitted time 2016-05-12 Hits1779Downloads1070 Comment 0

3. chinaXiv:201605.01489 [pdf]

MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes

Zhang, Peng; Wang, Jiajia; Huang, Da-Wei; He, Shunmin; Kang, Jun-Yan; Gou, Lan-Tao; Dai, Peng; Liu, Mo-Fang; Kang, Jun-Yan; Gou, Lan-Tao; Dai, Peng; Liu, Mo-Fang; Skogerboe, Geir; Chen, Runsheng; Xue, Yuanchao; Fu, Xiang-Dong; Xue, Yuanchao; Fu, Xiang-Dong
Subjects: Biology >> Biophysics >> Cell Biology

The piRNA machinery is known for its role in mediating epigenetic silencing of transposons. Recent studies suggest that this function also involves piRNA-guided cleavage of transposon-derived transcripts. As many piRNAs also appear to have the capacity to target diverse mRNAs, this raises the intriguing possibility that piRNAs may act extensively as siRNAs to degrade specific mRNAs. To directly test this hypothesis, we compared mouse PIWI (MIWI)-associated piRNAs with experimentally identified cleaved mRNA fragments from mouse testes, and observed cleavage sites that predominantly occur at position 10 from the 5' end of putative targeting piRNAs. We also noted strong biases for U and A residues at nucleotide positions 1 and 10, respectively, in both piRNAs and mRNA fragments, features that resemble the pattern of piRNA amplification by the 'ping-pong' cycle. Through mapping of MIWI-RNA interactions by CLIP-seq and gene expression profiling, we found that many potential piRNA-targeted mRNAs directly interact with MIWI and show elevated expression levels in the testes of Miwi catalytic mutant mice. Reporter-based assays further revealed the importance of base pairing between piRNAs and mRNA targets and the requirement for both the slicer activity and piRNA-loading ability of MIWI in piRNA-mediated target repression. Importantly, we demonstrated that proper turnover of certain key piRNA targets is essential for sperm formation. Together, these findings reveal the siRNA-like function of the piRNA machinery in mouse testes and its central requirement for male germ cell development and maturation.

submitted time 2016-05-12 Hits1565Downloads988 Comment 0

4. chinaXiv:201605.01481 [pdf]

LSY-2 is essential for maintaining the germ-soma distinction in C-elegans

Lin, Long; Lin, Long; Yan, Libo; Zhao, Yu; Lin, Long; Li, Yuping; Zhang, Gangming; Zhang, Hong
Subjects: Biology >> Biophysics >> Cell Biology

The mechanisms that specify and maintain the characteristics of germ cells during animal development are poorly understood. In this study, we demonstrated that loss of function of the zinc-finger gene lsy-2 results in various somatic cells adopting germ cells characteristics, including expression of germline-specific P granules, enhanced RNAi activity and transgene silencing. The soma to germ transformation in lsy-2 mutants requires the activities of multiple chromatin remodeling complexes, including the MES-4 complex and the ISW-1 complex. The distinct germline-specific features in somatic cells and the gene expression profile indicate that LSY-2 acts in the Mec complex in this process. Our study demonstrated that lsy-2 functions in the maintenance of the soma-germ distinction.

submitted time 2016-05-12 Hits1521Downloads898 Comment 0

5. chinaXiv:201605.01478 [pdf]

Impaired maturation of large dense-core vesicles in muted-deficient adrenal chromaffin cells

Hao, Zhenhua; Feng, Yaqin; Ma, Jing; Li, Wei; Hao, Zhenhua; Wei, Lisi; Chen, Xiaowei; Zhou, Zhuan; Chen, Liangyi; Wei, Lisi; Chen, Xiaowei; Zhou, Zhuan; Chen, Liangyi; Feng, Yaqin; Du, Wen; Li, Wei
Subjects: Biology >> Biophysics >> Cell Biology

The large dense-core vesicle (LDCV), a type of lysosome-related organelle, is involved in the secretion of hormones and neuropeptides in specialized secretory cells. The granin family is a driving force in LDCV biogenesis, but the machinery for granin sorting to this biogenesis pathway is largely unknown. The mu mutant mouse, which carries a spontaneous null mutation on the Muted gene (also known as Bloc1s5), which encodes a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), is a mouse model of Hermansky-Pudlak syndrome. Here, we found that LDCVs were enlarged in mu adrenal chromaffin cells. Chromogranin A (CgA, also known as CHGA) was increased in mu adrenals and muted-knockdown cells. The increased CgA in mu mice was likely due a failure to export this molecule out of immature LDCVs, which impairs LDCV maturation and docking. In mu chromaffin cells, the size of readily releasable pool and the vesicle release frequency were reduced. Our studies suggest that the muted protein is involved in the selective export of CgA during the biogenesis of LDCVs.

submitted time 2016-05-12 Hits1633Downloads999 Comment 0

6. chinaXiv:201605.01470 [pdf]

Brahma regulates the Hippo pathway activity through forming complex with Yki-Sd and regulating the transcription of Crumbs

Zhu, Ye; Wang, Yadong; Pei, Chunli; Yuan, Zengqiang; Zhang, Peng; Li, Dong; Liu, Song; Zhang, Lei
Subjects: Biology >> Biophysics >> Cell Biology

The Hippo signaling pathway restricts organ size by inactivating the Yorkie (Yki)/Yes-associated protein (YAP) family proteins. The oncogenic Yki/YAP transcriptional coactivator family promotes tissue growth by activating target gene transcription, but the regulation of Yki/YAP activation remains elusive. In mammalian cells, we identified Brg1, a major subunit of chromatin-remodeling SWI/SNF family proteins, which interacts with YAP. This finding led us to investigate the in vivo functional interaction of Yki and Brahma (Brm), the Drosophila homolog of Brg1. We found that Brm functions at the downstream of Hippo pathway and interacts with Yki and Scalloped (Sd) to promotes Yki-dependent transcription and tissue growth. Furthermore, we demonstrated that Brm is required for the Crumbs (Crb) dysregulation-induced Yki activation. Interestingly, we also found that crb is a downstream target of Yki-Brm complex. Brm physically binds to the promoter of crb and regulates its transcription through Yki. Together, we showed that Brm functions as a critical regulator of Hippo signaling during tissue growth and plays an important role in the feedback loop between Crb and Yki. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

submitted time 2016-05-12 Hits1582Downloads847 Comment 0

7. chinaXiv:201605.01469 [pdf]

Dynamic Phosphorylation of CENP-A at Ser68 Orchestrates Its Cell-Cycle-Dependent Deposition at Centromeres

Yu, Zhouliang; Zhou, Xiang; Wang, Wenjing; Deng, Wenqiang; Fang, Junnan; Hu, Hao; Wang, Zichen; Cui, Lei; Shen, Jing; Ou, Guangshuo; Yang, Na; Chen, Ping; Xu, Rui-Ming; Li, Guohong; Yu, Zhouliang; Deng, Wenqiang; Fang, Junnan; Hu, Hao; Peng, Shengyi; Li, Shangze
Subjects: Biology >> Biophysics >> Cell Biology

The H3 histone variant CENP-A is an epigenetic marker critical for the centromere identity and function. However, the precise regulation of the spatiotemporal deposition and propagation of CENP-A at centromeres during the cell cycle is still poorly understood. Here, we show that CENP-A is phosphorylated at Ser68 during early mitosis by Cdk1. Our results demonstrate that phosphorylation of Ser68 eliminates the binding of CENP-A to the assembly factor HJURP, thus preventing the premature loading of CENP-A to the centromere prior to mitotic exit. Because Cdk1 activity is at its minimum at the mitotic exit, the ratio of Cdk1/PP1 alpha activity changes in favor of Ser68 dephosphorylation, thus making CENP-A available for centromeric deposition by HJURP. Thus, we reveal that dynamic phosphorylation of CENP-A Ser68 orchestrates the spatiotemporal assembly of newly synthesized CENP-A at active centromeres during the cell cycle.

submitted time 2016-05-12 Hits1550Downloads877 Comment 0

8. chinaXiv:201605.01466 [pdf]

Structural insights into the catalytic mechanism of aldehyde-deformylating oxygenases

Jia, Chenjun; Li, Mei; Zhang, Hongmei; Cao, Peng; Pan, Xiaowei; Chang, Wenrui; Li, Jianjun; Zhang, Jingjing; Lu, Xuefeng; Jia, Chenjun; Zhang, Jingjing
Subjects: Biology >> Biophysics >> Cell Biology

The fatty alk(a/e)ne biosynthesis pathway found in cyanobacteria gained tremendous attention in recent years as a promising alternative approach for biofuel production. Cyanobacterial aldehyde-deformylating oxygenase (cADO), which catalyzes the conversion of C-n fatty aldehyde to its corresponding Cn-1 alk(a/e)ne, is a key enzyme in that pathway. Due to its low activity, alk(a/e)ne production by cADO is an inefficient process. Previous biochemical and structural investigations of cADO have provided some information on its catalytic reaction. However, the details of its catalytic processes remain unclear. Here we report five crystal structures of cADO from the Synechococcus elongates strain PCC7942 in both its iron-free and iron-bound forms, representing different states during its catalytic process. Structural comparisons and functional enzyme assays indicate that Glu144, one of the iron-coordinating residues, plays a vital role in the catalytic reaction of cADO. Moreover, the helix where Glu144 resides exhibits two distinct conformations that correlates with the different binding states of the di-iron center in cADO structures. Therefore, our results provide a structural explanation for the highly labile feature of cADO di-iron center, which we proposed to be related to its low enzymatic activity. On the basis of our structural and biochemical data, a possible catalytic process of cADO was proposed, which could aid the design of cADO with improved activity.

submitted time 2016-05-12 Hits1549Downloads865 Comment 0

9. chinaXiv:201605.01464 [pdf]

Regenerative medicine: targeted genome editing in vivo

Wang, Lixia; Liu, Guang-Hui; Wu, Jun; Belmonte, Juan Carlos Izpisua; Fang, Weiwei; Liu, Guang-Hui; Liu, Guang-Hui
Subjects: Biology >> Biophysics >> Cell Biology

The CRISPR/Cas system has proven to be a powerful gene editing tool both in vitro and in vivo. A recent flurry of studies of in vivo gene editing using the CRISPR/Cas system bring bright prospects in creating animal models and targeted gene therapy of human genetic diseases.

submitted time 2016-05-12 Hits1563Downloads889 Comment 0

10. chinaXiv:201605.01461 [pdf]

Guidelines for monitoring autophagy in Caenorhabditis elegans

Zhang, Hong; Guo, Bin; Lin, Long; Lu, Qun; Wu, Fan; Chang, Jessica T.; Hansen, Malene; Kumsta, Caroline; Lapierre, Louis R.; Jia, Kailiang; Kovacs, Attila L.; Legouis, Renaud; Melendez, Alicia; Melendez, Alicia; O'Rourke, Eyleen J.; Sato, Ken; Sato, Miyuki; Wang, Xiaochen
Subjects: Biology >> Biophysics >> Cell Biology

The cellular recycling process of autophagy has been extensively characterized with standard assays in yeast and mammalian cell lines. In multicellular organisms, numerous external and internal factors differentially affect autophagy activity in specific cell types throughout the stages of organismal ontogeny, adding complexity to the analysis of autophagy in these metazoans. Here we summarize currently available assays for monitoring the autophagic process in the nematode C. elegans. A combination of measuring levels of the lipidated Atg8 ortholog LGG-1, degradation of well-characterized autophagic substrates such as germline P granule components and the SQSTM1/p62 ortholog SQST-1, expression of autophagic genes and electron microscopy analysis of autophagic structures are presently the most informative, yet steady-state, approaches available to assess autophagy levels in C. elegans. We also review how altered autophagy activity affects a variety of biological processes in C. elegans such as L1 survival under starvation conditions, dauer formation, aging, and cell death, as well as neuronal cell specification. Taken together, C. elegans is emerging as a powerful model organism to monitor autophagy while evaluating important physiological roles for autophagy in key developmental events as well as during adulthood.

submitted time 2016-05-12 Hits1439Downloads939 Comment 0

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