Cell biology

  • Article
    | Open Access

    Proximity labeling is used to map and discover proteins in specific subcellular compartments. Here the authors combine APEX-mediated proximity labeling with organic-aqueous phase separation to identify nuclear, nucleolar, and outer mitochondrial membrane RNA binding proteins.

    • Wei Qin
    • , Samuel A. Myers
    •  & Alice Y. Ting
  • Article
    | Open Access

    Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling.

    • Seungyong Lee
    • , Charles Hwang
    •  & Benjamin Levi
  • Article
    | Open Access

    Bone morphogenetic protein (BMP) receptors are single pass transmembrane serine/threonine kinases that form tetrameric complexes comprised of two type I and two type II BMP receptors. Here the authors characterize a structure of an active type I/type II kinase tetramer providing insight into molecular mechanism driving ligand-induced signaling.

    • Christopher Agnew
    • , Pelin Ayaz
    •  & Natalia Jura
  • Article
    | Open Access

    Diabetes is characterized by dysfunction and loss of beta-cells, and promoting beta-cell survival is of therapeutic interest. Here the authors show that Large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, induces beta-cell failure through mTORC1 hyperactivation and autophagic flux suppression.

    • Ting Yuan
    • , Karthika Annamalai
    •  & Amin Ardestani
  • Article
    | Open Access

    Treating malignant pleural mesothelioma (MpM) is challenging due to a lack of druggable genes, but other molecular features could be clinically useful. Here the authors profile mRNA translation dysregulation in MpM cell lines using polysome profiling, and identify mTORC1 and 2 as potential pharmacological targets.

    • Stefano Grosso
    • , Alberto Marini
    •  & Anne E. Willis
  • Article
    | Open Access

    Germline mutations in BRCA1 or BRCA2 tumour suppressor genes predispose to different cancers, as does oncogene activation. Here the authors reveal that aberrant transcription of specific genes triggered by activation of the oncogene β-catenin causes replication failure and cell death in the context of BRCA1/2 deficiency.

    • Rebecca A. Dagg
    • , Gijs Zonderland
    •  & Madalena Tarsounas
  • Article
    | Open Access

    The sperm head-to-tail coupling apparatus ensures sperm head-tail integrity, but mechanistic insights remain limited. Here the authors demonstrate that CENTLEIN links and controls the interaction between SUN5 and PMFBP1, indicating that its impairments might be associated with acephalic spermatozoa syndrome.

    • Ying Zhang
    • , Chao Liu
    •  & Li Yuan
  • Article
    | Open Access

    Cellular cholesterol levels are tightly regulated. Here, the authors show that the hedgehog signalling receptor PTCH is a cholesterol transporter. Reduction in PTCH activity leads to cellular cholesterol accumulation, changes in nuclear hormone receptor activity and fatty acid metabolism.

    • Carla E. Cadena del Castillo
    • , J. Thomas Hannich
    •  & Anne Spang
  • Article
    | Open Access

    Lipid accumulation in the liver leads to nonalcoholic fatty liver disease (NAFLD) that is a risk factor for developing hepatocellular carcinoma (HCC). Here, the authors show that activation of the translation initiation factor eIF6 promotes lipid accumulation in the liver and targeting eIF6 in murine models reduces NAFLD and associated HCC.

    • Alessandra Scagliola
    • , Annarita Miluzio
    •  & Stefano Biffo
  • Article
    | Open Access

    The identification of response biomarkers for surgery, chemotherapy and immune checkpoint therapy in bladder cancer is crucial. Here, single nuclei RNA sequencing and spatial profiling identify a cancer cell population expressing Neural Type Cadherin 2 that associates with distinct treatment outcomes.

    • Kenneth H. Gouin III
    • , Nathan Ing
    •  & Dan Theodorescu
  • Article
    | Open Access

    UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

    • Davide Pradella
    • , Gianluca Deflorian
    •  & Claudia Ghigna
  • Article
    | Open Access

    Variants of the extracellular chaperone Clusterin are associated with Alzheimer’s disease (AD) and Clusterin levels are elevated in AD patient brains. Here, the authors show that Clusterin binds to oligomeric Tau, which enhances the seeding capacity of Tau aggregates upon cellular uptake. They also demonstrate that Tau/Clusterin complexes enter cells via the endosomal pathway, resulting in damage to endolysosomes and entry into the cytosol, where they induce the aggregation of endogenous, soluble Tau.

    • Patricia Yuste-Checa
    • , Victoria A. Trinkaus
    •  & F. Ulrich Hartl
  • Article
    | Open Access

    NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.

    • Huibing Wang
    • , Weiwei Qi
    •  & Junying Yuan
  • Article
    | Open Access

    The nature of the mitochondrial permeability transition pore (PTP) is still under debate. Here, through genetically modified F-ATP synthase, the authors show that PTP formation can be mediated by F-ATP synthase or by adenine nucleotide translocator, suggesting the existence of distinct but related permeability pathways.

    • Andrea Carrer
    • , Ludovica Tommasin
    •  & Paolo Bernardi
  • Article
    | Open Access

    Hyaluronan is a naturally occurring linear polysaccharide that together with collagens, enzymes, and glycoproteins forms the extracellular matrix. Here the authors show that adipose tissue overproduction of Hyaluronan reduces fat accumulation in mice fed high-fat diet and improves systemic glucose homeostasis.

    • Yi Zhu
    • , Na Li
    •  & Philipp E. Scherer
  • Article
    | Open Access

    RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.

    • Chloé Maurizy
    • , Claire Abeza
    •  & Bérengère Pradet-Balade
  • Article
    | Open Access

    Coenzyme Q (CoQ) is a lipid made in the inner mitochondrial membrane with antioxidant roles throughout the cell, but regulation of its cellular distribution is unclear. Here the authors identify two proteins that have reciprocal CoQ trafficking functions to help coordinate CoQ localization in yeast.

    • Zachary A. Kemmerer
    • , Kyle P. Robinson
    •  & David J. Pagliarini
  • Article
    | Open Access

    Epithelial cells that organise into structures that contain a lumen are polarised. Here, the authors show that the short intracellular domain of transmembrane protein CD13 is required to capture endosomes at the apical site and is required for the polarisation of cells.

    • Li-Ting Wang
    • , Abira Rajah
    •  & Luke McCaffrey
  • Article
    | Open Access

    Salmonella secretes the effector protein SopD into the host cell cytoplasm, leading to scission of the plasma membrane through unclear mechanisms. Here, Boddy et al. show that SopD binds to and inhibits the small GTPase Rab10, thus promoting removal of Rab10 and recruitment of dynamin-2 to drive plasma membrane scission.

    • Kirsten C. Boddy
    • , Hongxian Zhu
    •  & John H. Brumell
  • Article
    | Open Access

    The authors have recently developed molecular force microscopy (MFM) which uses fluorescence polarisation to measure cell-surface receptor force orientation. Here they show that structured illumination microscopes, which inherently use fluorescence polarisation, can be used for MFM in a turn-key manner.

    • Aaron Blanchard
    • , J. Dale Combs
    •  & Khalid Salaita
  • Article
    | Open Access

    While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.

    • Jenna Giubilaro
    • , Doris A. Schuetz
    •  & Stéphane A. Laporte
  • Article
    | Open Access

    Glucocorticoids are associated with stress. Here, the authors show that high levels of glucocorticoid stress promote secretory autophagy of matrix metalloproteinase 9 via a stress responsive chaperone, increasing brain-derived neurotrophic factor processing and potentially altering adult synaptic plasticity.

    • Silvia Martinelli
    • , Elmira A. Anderzhanova
    •  & Nils C. Gassen
  • Article
    | Open Access

    Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth.

    • Virginia Giuliani
    • , Meredith A. Miller
    •  & Timothy P. Heffernan
  • Article
    | Open Access

    Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.

    • Marie P. Schützmann
    • , Filip Hasecke
    •  & Wolfgang Hoyer
  • Article
    | Open Access

    Here, the authors show that microglia depletion results in unstable wakefulness and altered levels of ceramide, influencing microglia in the mouse thalamic reticular nucleus (TRN). Stable wakefulness can be restored by activation of the TRN or inhibition of ceramide production in the mouse brain.

    • Hanxiao Liu
    • , Xinxing Wang
    •  & Qiaojie Xiong
  • Article
    | Open Access

    Hedgehog signaling is essential for bone formation. Here, the authors show that the transmembrane protein SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts, suggesting it may be a potential therapeutic target to enhance bone formation.

    • Jun Sun
    • , Dong Yeon Shin
    •  & Matthew B. Greenblatt
  • Article
    | Open Access

    UBE2W catalyzes the ubiquitination of protein N-termini but its substrate spectrum is largely unknown. Here, the authors discover mAbs selective for peptides derived from N-terminally ubiquitinated proteins, solve the structure of a peptide-bound mAb and apply the mAbs to map endogenous UBE2W substrates by proteomics.

    • Christopher W. Davies
    • , Simon E. Vidal
    •  & James T. Koerber
  • Article
    | Open Access

    Cytokinetic ring constriction during cell division requires actin but curiously is independent of myosin in many organisms. Here, the authors show that anillin, a protein enriched in the contractile ring, is a non-motor actin crosslinker that generates contractile force in lieu of a molecular motor.

    • Ondřej Kučera
    • , Valerie Siahaan
    •  & Zdenek Lansky
  • Article
    | Open Access

    S-acylation is the post-translational covalent attachment of fatty acids (FA) onto cysteines. Nuskova et al. find that exposure of cells to different FAs affects which FA is used to S-acylate GNAI proteins, thereby altering GNAI function and EGFR pathway activation, linking metabolism to signaling.

    • Hana Nůsková
    • , Marina V. Serebryakova
    •  & Aurelio A. Teleman
  • Article
    | Open Access

    Endoplasmic reticulum (ER)-interorganelle membrane contact sites have emerged as key regulators of organelle dynamics. Here, the authors report that the ER-resident protein SNX19 mediates ER-endolysosome membrane contacts to maintain the perinuclear distribution of endolysosomes and restrict their motility.

    • Amra Saric
    • , Spencer A. Freeman
    •  & Juan S. Bonifacino
  • Article
    | Open Access

    Patients with Cornelia de Lange Syndrome (CdLS) often have mutations in cohesin and its regulators; however, the molecular mechanism driving CdLS phenotypes is not well established. Here the authors reveal system skeletal organization genes are downregulated and show that cohesin and its loader Nipbl have altered and decreased genome-wide localization.

    • Patricia Garcia
    • , Rita Fernandez-Hernandez
    •  & Ethel Queralt
  • Article
    | Open Access

    Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.

    • Hao Ding
    • , Linda Xiaoyan Li
    •  & Xiaogang Li
  • Article
    | Open Access

    Environmental and genetic risk factors affect the distal airway epithelium in idiopatic pulmonary fibrosis (IPF) but the role of the epithelium in IPF remains unclear. Here the authors show that pathologic activation of the ERBB-YAP axis induces dynamic and structural dysfunction in the distal airway epithelium eliciting a pro-fibrotic phenotype in mesenchymal cells.

    • Ian T. Stancil
    • , Jacob E. Michalski
    •  & David A. Schwartz
  • Article
    | Open Access

    Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.

    • Sofía Cabezudo
    • , Maria Sanz-Flores
    •  & Catalina Ribas
  • Article
    | Open Access

    BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.

    • Riccardo Biavasco
    • , Emanuele Lettera
    •  & Eugenio Montini
  • Article
    | Open Access

    The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.

    • Lindsey Mayes-Hopfinger
    • , Aura Enache
    •  & Emad S. Alnemri
  • Article
    | Open Access

    Assembly of the mitoribosome requires assistance from numerous specialized factors. Here, structures of the human 39S late assembly intermediates identify several assembly factors which keep the 16S rRNA in immature conformations, and reveal deacylated tRNA in the ribosomal E-site, suggesting a role in 39S assembly.

    • Jingdong Cheng
    • , Otto Berninghausen
    •  & Roland Beckmann
  • Article
    | Open Access

    The transmembrane protein Wntless (WLS) is essential for the secretion of Wnt proteins, which are signaling molecules of the Wnt signaling pathways. Here, the authors present the 2.2 Å cryo-EM structure of human WLS in complex with Wnt3a and discuss mechanistic implications for the palmitoleoylation of Wnt3a that is required for WLS mediated Wnt secretion.

    • Qing Zhong
    • , Yanyu Zhao
    •  & Dan Ma
  • Article
    | Open Access

    Calcium signals initiated by IP3 receptors in ER membranes regulate most cellular activities. Here, the authors show that KRas-induced actininteracting protein (KRAP) tethers a small subset of IP3 receptors to actin and licenses them to evoke cytosolic calcium signals.

    • Nagendra Babu Thillaiappan
    • , Holly A. Smith
    •  & Colin W. Taylor
  • Article
    | Open Access

    Cells in many tissues fuse into syncytia acquiring new functions. By investigating whether physical remodelling promotes differentiation, here, the authors show that plasma membrane diminution post-fusion causes transient nutrient stress that inhibits YAP1 activity and may reduce proliferation-promoting transcription.

    • Daniel Feliciano
    • , Carolyn M. Ott
    •  & Jennifer Lippincott-Schwartz
  • Article
    | Open Access

    In neurons and other cells, contacts between organelles regulates function and subcellular organization, but the precise mechanisms and effects are unclear. Here the authors show that endoplasmic reticulum (ER) tubules in the soma of neurons regulate lysosome localization and function by regulating lysosomal fission, suggesting a role for ER – lysosome inter-organelle membrane contact sites in lysosomal axonal availability.

    • Nazmiye Özkan
    • , Max Koppers
    •  & Ginny G. Farías