Coordinated calcium signalling in cochlear sensory and non-sensory cells refines afferent innervation of outer hair cells
Outer hair cells (OHCs) are highly specialized sensory cells conferring the fine-tuning and high sensitivity of the mammalian cochlea to acoustic stimuli. Here, by genetically manipulating spontaneous Ca2+ signalling in mice in vivo, through a period of early postnatal development, we find that the refinement of OHC afferent innervation is regulated by complementary spontaneous Ca2+ signals originating in OHCs and non-sensory cells. OHCs fire spontaneous Ca2+ action potentials during a narrow period of neonatal development. Simultaneously, waves of Ca2+ activity in the non-sensory cells of the greater epithelial ridge...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Ceriani, F., Hendry, A., Jeng, J.-Y., Johnson, S. L., Stephani, F., Olt, J., Holley, M. C., Mammano, F., Engel, J., Kros, C. J., Simmons, D. D., Marcotti, W. Tags: Development & Differentiation, Membrane & Intracellular Transport Articles Source Type: research
TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination
Regulatory T cells (Tregs) are crucial mediators of immune control. The characteristic gene expression and suppressive functions of Tregs depend considerably on the stable expression and activity of the transcription factor FOXP3. Transcriptional regulation of the Foxp3 gene has been studied in depth, but both the expression and function of this factor are also modulated at the protein level. However, the molecular players involved in posttranslational FOXP3 regulation are just beginning to be elucidated. Here, we found that TRAF6-deficient Tregs were dysfunctional in vivo; mice with Treg-restricted deletion of TRAF6 ...
Source: EMBO Journal - April 24, 2019 Category: Molecular Biology Authors: Ni, X., Kou, W., Gu, J., Wei, P., Wu, X., Peng, H., Tao, J., Yan, W., Yang, X., Lebid, A., Park, B. V., Chen, Z., Tian, Y., Fu, J., Newman, S., Wang, X., Shen, H., Li, B., Blazar, B. R., Wang, X., Barbi, J., Pan, F., Lu, L. Tags: Cancer, Immunology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Pancreatic development: one cell at a (pseudo)time
Gaining a comprehensive understanding of the principles guiding lineage differentiation during organogenesis is a challenge. In this issue, Yu et al (2019) tackle this venture by taking advantage of single-cell transcriptomic analyses and multiple mouse genetic tools. Their work provides new insights into pancreatic endocrine and exocrine cell differentiation landscapes and identifies new pathways regulating pancreatic lineage allocation in vivo. (Source: EMBO Journal)
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Liu, Z., Sneddon, J. B. Tags: Development & Differentiation, Systems & Computational Biology News [amp ] Views Source Type: research
To Fis or not to Fuse? This is the question!
This study highlights the limitation of categorizing mitochondrial dynamics proteins based on architecture measurements, given the general tendency to associate fragmentation with activation of fission. (Source: EMBO Journal)
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Liesa, M., Van der Bliek, A., Shirihai, O. S. Tags: Membrane & Intracellular Transport News [amp ] Views Source Type: research
SUMOylation promotes protective responses to DNA-protein crosslinks
DNA-protein crosslinks (DPCs) are highly cytotoxic lesions that obstruct essential DNA transactions and whose resolution is critical for cell and organismal fitness. However, the mechanisms by which cells respond to and overcome DPCs remain incompletely understood. Recent studies unveiled a dedicated DPC repair pathway in higher eukaryotes involving the SprT-type metalloprotease SPRTN/DVC1, which proteolytically processes DPCs during DNA replication in a ubiquitin-regulated manner. Here, we show that chemically induced and defined enzymatic DPCs trigger potent chromatin SUMOylation responses targeting the crosslinked prote...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Borgermann, N., Ackermann, L., Schwertman, P., Hendriks, I. A., Thijssen, K., Liu, J. C., Lans, H., Nielsen, M. L., Mailand, N. Tags: DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Slicing and dicing viruses: antiviral RNA interference in mammals
To protect against the harmful consequences of viral infections, organisms are equipped with sophisticated antiviral mechanisms, including cell-intrinsic means to restrict viral replication and propagation. Plant and invertebrate cells utilise mostly RNA interference (RNAi), an RNA-based mechanism, for cell-intrinsic immunity to viruses while vertebrates rely on the protein-based interferon (IFN)-driven innate immune system for the same purpose. The RNAi machinery is conserved in vertebrate cells, yet whether antiviral RNAi is still active in mammals and functionally relevant to mammalian antiviral defence is intensely deb...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Maillard, P. V., van der Veen, A. G., Poirier, E. Z., Reis e Sousa, C. Tags: Immunology, RNA Biology Review Source Type: research
Phosphatidylinositol 4,5-bisphosphate controls Rab7 and PLEKMH1 membrane cycling during autophagosome-lysosome fusion
The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP-bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7-positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)P2 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affec...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Baba, T., Toth, D. J., Sengupta, N., Kim, Y. J., Balla, T. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport Articles Source Type: research
Defining multistep cell fate decision pathways during pancreatic development at single-cell resolution
This study provides key insights into the regulatory mechanisms underlying cell fate choice and stepwise cell fate commitment and can be used as a resource to guide the induction of functional islet lineage cells from stem cells in vitro. (Source: EMBO Journal)
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Yu, X.-X., Qiu, W.-L., Yang, L., Zhang, Y., He, M.-Y., Li, L.-C., Xu, C.-R. Tags: Development & Differentiation, Methods & Resources, Systems & Computational Biology Source Type: research
Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites
SREBPs are master regulators of lipid homeostasis and undergo sterol-regulated export from ER to Golgi apparatus for processing and activation via COPII-coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet-associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP-Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb b...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Su, L., Zhou, L., Chen, F.-J., Wang, H., Qian, H., Sheng, Y., Zhu, Y., Yu, H., Gong, X., Cai, L., Yang, X., Xu, L., Zhao, T.-J., Li, J. Z., Chen, X.-W., Li, P. Tags: Membrane & Intracellular Transport, Metabolism Articles Source Type: research
A spatiotemporally regulated transcriptional complex underlies heteroblastic development of leaf hairs in Arabidopsis thaliana
Heteroblasty refers to a phenomenon that a plant produces morphologically or functionally different lateral organs in an age-dependent manner. In the model plant Arabidopsis thaliana, the production of trichomes (epidermal leaf hairs) on the abaxial (lower) side of leaves is a heteroblastic mark for the juvenile-to-adult transition. Here, we show that the heteroblastic development of abaxial trichomes is regulated by a spatiotemporally regulated complex comprising the leaf abaxial fate determinant (KAN1) and the developmental timer (miR172-targeted AP2-like proteins). We provide evidence that a short-distance chromatin loo...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Wang, L., Zhou, C.-M., Mai, Y.-X., Li, L.-Z., Gao, J., Shang, G.-D., Lian, H., Han, L., Zhang, T.-Q., Tang, H.-B., Ren, H., Wang, F.-X., Wu, L.-Y., Liu, X.-L., Wang, C.-S., Chen, E.-W., Zhang, X.-N., Liu, C., Wang, J.-W. Tags: Development & Differentiation, Plant Biology, Transcription Articles Source Type: research
The long noncoding RNA ROCKI regulates inflammatory gene expression
Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B Streptococcus. We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and I...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Zhang, Q., Chao, T.-C., Patil, V. S., Qin, Y., Tiwari, S. K., Chiou, J., Dobin, A., Tsai, C.-M., Li, Z., Dang, J., Gupta, S., Urdahl, K., Nizet, V., Gingeras, T. R., Gaulton, K. J., Rana, T. M. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction, RNA Biology Articles Source Type: research
Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery
Mitochondrial dynamics is important for life. At center stage for mitochondrial dynamics, the balance between mitochondrial fission and fusion is a set of dynamin-related GTPases that drive mitochondrial fission and fusion. Fission is executed by the GTPases Drp1 and Dyn2, whereas the GTPases Mfn1, Mfn2, and OPA1 promote fusion. Recruitment of Drp1 to mitochondria is a critical step in fission. In yeast, Fis1p recruits the Drp1 homolog Dnm1p to mitochondria through Mdv1p and Caf4p, but whether human Fis1 (hFis1) promotes fission through a similar mechanism as in yeast is not established. Here, we show that hFis1-mediated m...
Source: EMBO Journal - April 14, 2019 Category: Molecular Biology Authors: Yu, R., Jin, S.-B., Lendahl, U., Nister, M., Zhao, J. Tags: Membrane & Intracellular Transport Articles Source Type: research
Bub1--the zombie protein that CRISPR cannot kill
The conserved Bub1 kinase was proposed to be non-essential for the mitotic spindle assembly checkpoint based on recent findings that knocking-out Bub1 by CRISPR/Cas9 did not impair checkpoint function in human cells. New studies now demonstrate that CRISPR/Cas9 Bub1 knockout cells still express low levels of Bub1 protein and that only removal of this remaining Bub1 pool by RNA interference substantially weakens spindle assembly checkpoint signaling. (Source: EMBO Journal)
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Meraldi, P. Tags: Cell Cycle, Chromatin, Epigenetics, Genomics & Functional Genomics, Methods & Resources News [amp ] Views Source Type: research
Revealing chromatin organization in metaphase chromosomes
The local structural organization of chromatin in mitotic chromosomes is not well understood. A new cryo-electron tomography study from the Daban laboratory (Chicano et al, 2019) reveals that mitotic chromatin isolated from human cells can assume a plate-like fine structure, containing layers of interdigitated nucleosomes. Such a multilayered organization suggests a possible model for mitotic chromatin compaction. (Source: EMBO Journal)
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Fierz, B. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Structural Biology News [amp ] Views Source Type: research
Hfq-dependent mRNA unfolding promotes sRNA-based inhibition of translation
Small RNAs post-transcriptionally regulate many processes in bacteria. Base-pairing of sRNAs near ribosome-binding sites in mRNAs inhibits translation, often requiring the RNA chaperone Hfq. In the canonical model, Hfq simultaneously binds sRNAs and mRNA targets to accelerate pairing. Here, we show that the Escherichia coli sRNAs OmrA and OmrB inhibit translation of the diguanylate cyclase DgcM (previously: YdaM), a player in biofilm regulation. In OmrA/B repression of dgcM, Hfq is not required as an RNA interaction platform, but rather unfolds an inhibitory RNA structure that impedes OmrA/B binding. This restructuring inv...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Hoekzema, M., Romilly, C., Holmqvist, E., Wagner, E. G. H. Tags: Microbiology, Virology & Host Pathogen Interaction, RNA Biology Articles Source Type: research
