Cell Reports

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Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions

Hsien-Yang Lee, Yong Huang, Nadine Bruneau, Patrice Roll, more

Cell Reports > 2012 > 1 > 1 > 2-12

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected...

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More than the Sum of Its Parts

Boyana Konforti

Cell Reports > 2012 > 1 > 1 > 1

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An Essential Role of Hrs/Vps27 in Endosomal Cholesterol Trafficking

Ximing Du, Abdulla S. Kazim, Andrew J. Brown, Hongyuan Yang

Cell Reports > 2012 > 1 > 1 > 29-35

The endosomal sorting complex required for transport (ESCRT) plays a crucial role in the degradation of ubiquitinated endosomal membrane proteins. Here, we report that Hrs, a key protein of the ESCRT-0 complex, is required for the transport of low-density lipoprotein-derived cholesterol from endosomes to the endoplasmic reticulum. This function of Hrs in cholesterol transport is distinct from its...

article

Premetazoan Origin of the Hippo Signaling Pathway

Arnau Sebé-Pedrós, Yonggang Zheng, Iñaki Ruiz-Trillo, Duojia Pan

Cell Reports > 2012 > 1 > 1 > 13-20

Nonaggregative multicellularity requires strict control of cell number. The Hippo signaling pathway coordinates cell proliferation and apoptosis and is a central regulator of organ size in animals. Recent studies have shown the presence of key members of the Hippo pathway in nonbilaterian animals, but failed to identify this pathway outside Metazoa. Through comparative analyses of recently sequenced...

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The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

Yun-Hee Youm, Thirumala-Devi Kanneganti, Bolormaa Vandanmagsar, Xuewei Zhu, more

Cell Reports > 2012 > 1 > 1 > 56-68

The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naive T cells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in ‘lipotoxic danger signals’ such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical...

article

Global Analysis of RNA Secondary Structure in Two Metazoans

Fan Li, Qi Zheng, Paul Ryvkin, Isabelle Dragomir, more

Cell Reports > 2012 > 1 > 1 > 69-82

The secondary structure of RNA is necessary for its maturation, regulation, processing, and function. However, the global influence of RNA folding in eukaryotes is still unclear. Here, we use a high-throughput, sequencing-based, structure-mapping approach to identify the paired (double-stranded RNA [dsRNA]) and unpaired (single-stranded RNA [ssRNA]) components of the Drosophila melanogaster and Caenorhabditis...

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Thermosensory and Nonthermosensory Isoforms of Drosophila melanogaster TRPA1 Reveal Heat-Sensor Domains of a ThermoTRP Channel

Lixian Zhong, Andrew Bellemer, Haidun Yan, Ken Honjo, more

Cell Reports > 2012 > 1 > 1 > 43-55

Specialized somatosensory neurons detect temperatures ranging from pleasantly cool or warm to burning hot and painful (nociceptive). The precise temperature ranges sensed by thermally sensitive neurons is determined by tissue-specific expression of ion channels of the transient receptor potential (TRP) family. We show here that in Drosophila, TRPA1 is required for the sensing of nociceptive heat....

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Mutation Hot Spots in Yeast Caused by Long-Range Clustering of Homopolymeric Sequences

Xin Ma, Maria V. Rogacheva, K.T. Nishant, Sarah Zanders, more

Cell Reports > 2012 > 1 > 1 > 36-42

Evolutionary theory assumes that mutations occur randomly in the genome; however, studies performed in a variety of organisms indicate the existence of context-dependent mutation biases. Sources of mutagenesis variation across large genomic contexts (e.g., hundreds of bases) have not been identified. Here, we use high-coverage whole-genome sequencing of a conditional mismatch repair mutant line of...

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Structure of the SecY Complex Unlocked by a Preprotein Mimic

Dilem Hizlan, Alice Robson, Sarah Whitehouse, Vicki A. Gold, more

Cell Reports > 2012 > 1 > 1 > 21-28

The Sec complex forms the core of a conserved machinery coordinating the passage of proteins across or into biological membranes. The bacterial complex SecYEG interacts with the ATPase SecA or translating ribosomes to translocate secretory and membrane proteins accordingly. A truncated preprotein competes with the physiological full-length substrate and primes the protein-channel complex for transport...

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Functional Consequences of Subunit Diversity in RNA Polymerases II and V

Ek Han Tan, Todd Blevins, Thomas S. Ream, Craig S. Pikaard

Cell Reports > 2012 > 1 > 3 > 208-214

Multisubunit RNA polymerases IV and V (Pol IV and Pol V) evolved as specialized forms of Pol II that mediate RNA-directed DNA methylation (RdDM) and transcriptional silencing of transposons, viruses, and endogenous repeats in plants. Among the subunits common to Arabidopsis thaliana Pols II, IV, and V are 93% identical alternative ninth subunits, NRP(B/D/E)9a and NRP(B/D/E)9b. The 9a and 9b subunit...

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FoldEco: A Model for Proteostasis in E. coli

Evan T. Powers, David L. Powers, Lila M. Gierasch

Cell Reports > 2012 > 1 > 3 > 265-276

To gain insight into the interplay of processes and species that maintain a correctly folded, functional proteome, we have developed a computational model called FoldEco. FoldEco models the cellular proteostasis network of the E. coli cytoplasm, including protein synthesis, degradation, aggregation, chaperone systems, and the folding characteristics of protein clients. We focused on E. coli because...

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Transient Noise Amplification and Gene Expression Synchronization in a Bistable Mammalian Cell-Fate Switch

Santhosh Palani, Casim A. Sarkar

Cell Reports > 2012 > 1 > 3 > 215-224

Progenitor cells within a clonal population show variable proclivity toward lineage commitment and differentiation. This cell-to-cell variability has been attributed to transcriptome-wide gene expression noise generated by fluctuations in the amount of cellular machinery and stochasticity in the biochemical reactions involved in protein synthesis. It therefore remains unclear how a signaling network,...

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VEGF-C Promotes Immune Tolerance in B16 Melanomas and Cross-Presentation of Tumor Antigen by Lymph Node Lymphatics

Amanda W. Lund, Fernanda V. Duraes, Sachiko Hirosue, Vidya R. Raghavan, more

Cell Reports > 2012 > 1 > 3 > 191-199

Tumor expression of the lymphangiogenic factor VEGF-C is correlated with metastasis and poor prognosis, and although VEGF-C enhances transport to the draining lymph node (dLN) and antigen exposure to the adaptive immune system, its role in tumor immunity remains unexplored. Here, we demonstrate that VEGF-C promotes immune tolerance in murine melanoma. In B16 F10 melanomas expressing a foreign antigen...

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Impaired Dendritic Expression and Plasticity of h-Channels in the fmr1−/y Mouse Model of Fragile X Syndrome

Darrin H. Brager, Arvin R. Akhavan, Daniel Johnston

Cell Reports > 2012 > 1 > 3 > 225-233

Despite extensive research into both synaptic and morphological changes, surprisingly little is known about dendritic function in fragile X syndrome (FXS). We found that the dendritic input resistance of CA1 neurons was significantly lower in fmr1 ^−/y versus wild-type mice. Consistent with elevated dendritic I _h , voltage sag, rebound, and resonance frequency were significantly higher...

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Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels

Rémi Peyronnet, Reza Sharif-Naeini, Joost H.A. Folgering, Malika Arhatte, more

Cell Reports > 2012 > 1 > 3 > 241-250

How renal epithelial cells respond to increased pressure and the link with kidney disease states remain poorly understood. Pkd1 knockout or expression of a PC2 pathogenic mutant, mimicking the autosomal dominant polycystic kidney disease, dramatically enhances mechanical stress-induced tubular apoptotic cell death. We show the presence of a stretch-activated K ⁺ channel dependent on the TREK-2...

article

Assembly Stoichiometry of the GluK2/GluK5 Kainate Receptor Complex

Andreas Reiner, Ryan J. Arant, Ehud Y. Isacoff

Cell Reports > 2012 > 1 > 3 > 234-240

Ionotropic glutamate receptors assemble as homo- or heterotetramers. One well-studied heteromeric complex is formed by the kainate receptor subunits GluK2 and GluK5. Retention motifs prevent trafficking of GluK5 homomers to the plasma membrane, but coassembly with GluK2 yields functional heteromeric receptors. Additional control over GluK2/GluK5 assembly seems to be exerted by the amino-terminal domains,...

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DnaK Functions as a Central Hub in the E. coli Chaperone Network

Giulia Calloni, Taotao Chen, Sonya M. Schermann, Hung-chun Chang, more

Cell Reports > 2012 > 1 > 3 > 251-264

Cellular chaperone networks prevent potentially toxic protein aggregation and ensure proteome integrity. Here, we used Escherichia coli as a model to understand the organization of these networks, focusing on the cooperation of the DnaK system with the upstream chaperone Trigger factor (TF) and the downstream GroEL. Quantitative proteomics revealed that DnaK interacts with at least ∼700 mostly cytosolic...

article

The X-ray Crystal Structure of Full-Length Human Plasminogen

Ruby H.P. Law, Tom Caradoc-Davies, Nathan Cowieson, Anita J. Horvath, more

Cell Reports > 2012 > 1 > 3 > 185-190

Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an...

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Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9

Michael A. Hadders, Doryen Bubeck, Pietro Roversi, Svetlana Hakobyan, more

Cell Reports > 2012 > 1 > 3 > 200-207

Activation of the complement system results in formation of membrane attack complexes (MACs), pores that disrupt lipid bilayers and lyse bacteria and other pathogens. Here, we present the crystal structure of the first assembly intermediate, C5b6, together with a cryo-electron microscopy reconstruction of a soluble, regulated form of the pore, sC5b9. Cleavage of C5 to C5b results in marked conformational...

article

Global Patterns of Tissue-Specific Alternative Polyadenylation in Drosophila

Peter Smibert, Pedro Miura, Jakub O. Westholm, Sol Shenker, more

Cell Reports > 2012 > 1 > 3 > 277-289

We analyzed the usage and consequences of alternative cleavage and polyadenylation (APA) in Drosophila melanogaster by using >1 billion reads of stranded mRNA-seq across a variety of dissected tissues. Beyond demonstrating that a majority of fly transcripts are subject to APA, we observed broad trends for 3′ untranslated region (UTR) shortening in the testis and lengthening in the central nervous...

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Cell Reports

Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions

More than the Sum of Its Parts

An Essential Role of Hrs/Vps27 in Endosomal Cholesterol Trafficking

Premetazoan Origin of the Hippo Signaling Pathway

The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

Global Analysis of RNA Secondary Structure in Two Metazoans

Thermosensory and Nonthermosensory Isoforms of Drosophila melanogaster TRPA1 Reveal Heat-Sensor Domains of a ThermoTRP Channel

Mutation Hot Spots in Yeast Caused by Long-Range Clustering of Homopolymeric Sequences

Structure of the SecY Complex Unlocked by a Preprotein Mimic

Functional Consequences of Subunit Diversity in RNA Polymerases II and V

FoldEco: A Model for Proteostasis in E. coli

Transient Noise Amplification and Gene Expression Synchronization in a Bistable Mammalian Cell-Fate Switch

VEGF-C Promotes Immune Tolerance in B16 Melanomas and Cross-Presentation of Tumor Antigen by Lymph Node Lymphatics

Impaired Dendritic Expression and Plasticity of h-Channels in the fmr1−/y Mouse Model of Fragile X Syndrome

Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels

Assembly Stoichiometry of the GluK2/GluK5 Kainate Receptor Complex

DnaK Functions as a Central Hub in the E. coli Chaperone Network

The X-ray Crystal Structure of Full-Length Human Plasminogen

Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9

Global Patterns of Tissue-Specific Alternative Polyadenylation in Drosophila

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