RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress

Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER-embedded RING finger protein 26 (RNF26) at the C-terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis.

[1]  Hiroyuki Arai,et al.  STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes , 2023, Nature Cell Biology.

[2]  S. Paludan,et al.  STING is ESCRTed to degradation by microautophagy , 2023, Nature Cell Biology.

[3]  G. Knott,et al.  Dynamics of CLIMP-63 S-acylation control ER morphology , 2023, Nature Communications.

[4]  G. Kroemer,et al.  Endoplasmic Reticulum Stress in Liver Diseases. , 2022, Hepatology.

[5]  Tom Shemesh,et al.  A role for endoplasmic reticulum dynamics in the cellular distribution of microtubules , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Molinari,et al.  ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum , 2022, Physiological reviews.

[7]  Pedro Carvalho,et al.  Order through destruction: how ER‐associated protein degradation contributes to organelle homeostasis , 2022, The EMBO journal.

[8]  C. Uetrecht,et al.  Caldendrin and myosin V regulate synaptic spine apparatus localization via ER stabilization in dendritic spines , 2021, The EMBO journal.

[9]  Christopher J. Obara,et al.  ER proteins decipher the tubulin code to regulate organelle distribution , 2021, Nature.

[10]  A. Brazma,et al.  The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences , 2021, Nucleic Acids Res..

[11]  M. Teh,et al.  Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis , 2021, Cancers.

[12]  Oriol Vinyals,et al.  Highly accurate protein structure prediction with AlphaFold , 2021, Nature.

[13]  Jun Ren,et al.  Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases , 2021, Nature Reviews Cardiology.

[14]  J. Neefjes,et al.  Mobile late endosomes modulate peripheral endoplasmic reticulum network architecture , 2021, EMBO reports.

[15]  J. Neefjes,et al.  The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal control over the endolysosomal pathway. , 2021, Cell reports.

[16]  J. Neefjes,et al.  The journey of Ca2+ through the cell – pulsing through the network of ER membrane contact sites , 2020, Journal of Cell Science.

[17]  D. Moore,et al.  Vimentin's side gig: Regulating cellular proteostasis in mammalian systems , 2020, Cytoskeleton.

[18]  M. Pajares,et al.  Type III intermediate filaments as targets and effectors of electrophiles and oxidants , 2020, Redox biology.

[19]  S. Köster,et al.  Vimentin intermediate filaments stabilize dynamic microtubules by direct interactions , 2020, Nature Communications.

[20]  Rik van der Kant,et al.  SKIP‐HOPS recruits TBC1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport , 2020, The EMBO journal.

[21]  Marcus J. Fantham,et al.  The structure and global distribution of the endoplasmic reticulum network are actively regulated by lysosomes , 2020, bioRxiv.

[22]  G. Charras,et al.  F-Actin Interactome Reveals Vimentin as a Key Regulator of Actin Organization and Cell Mechanics in Mitosis , 2020, Developmental cell.

[23]  L. Hendershot,et al.  Disposing of misfolded ER proteins: A troubled substrate's way out of the ER , 2020, Molecular and Cellular Endocrinology.

[24]  W. Prinz,et al.  The functional universe of membrane contact sites , 2019, Nature Reviews Molecular Cell Biology.

[25]  M. Molinari,et al.  ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress , 2019, Nature Communications.

[26]  Junjie Hu,et al.  Calumenin-1 Interacts with Climp63 to Cooperatively Determine the Luminal Width and Distribution of Endoplasmic Reticulum Sheets , 2019, iScience.

[27]  P. Janmey,et al.  Vimentin protects cells against nuclear rupture and DNA damage during migration , 2019, The Journal of cell biology.

[28]  M. Pajares,et al.  Vimentin filaments interact with the actin cortex in mitosis allowing normal cell division , 2019, Nature Communications.

[29]  J. Bonifacino,et al.  Lysosome Positioning Influences mTORC2 and AKT Signaling. , 2019, Molecular cell.

[30]  C. Hoogenraad,et al.  Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity , 2019, Neuron.

[31]  M. Steinmetz,et al.  Mechanisms of Motor-Independent Membrane Remodeling Driven by Dynamic Microtubules , 2019, Current Biology.

[32]  J. Hollien,et al.  Degradation of Blos1 mRNA by IRE1 repositions lysosomes and protects cells from stress , 2019, The Journal of cell biology.

[33]  S. Étienne-Manneville.  Cytoplasmic Intermediate Filaments in Cell Biology. , 2018, Annual review of cell and developmental biology.

[34]  Pedro Carvalho,et al.  Here, there, and everywhere: The importance of ER membrane contact sites , 2018, Science.

[35]  J. Lippincott-Schwartz,et al.  Interacting organelles. , 2018, Current opinion in cell biology.

[36]  N. Perrimon,et al.  Efficient proximity labeling in living cells and organisms with TurboID , 2018, Nature Biotechnology.

[37]  Samara L. Reck-Peterson,et al.  The cytoplasmic dynein transport machinery and its many cargoes , 2018, Nature Reviews Molecular Cell Biology.

[38]  Yuki Hayashi,et al.  Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD) , 2017, Journal of Cell Science.

[39]  J. Holthuis,et al.  Membrane contact sites, ancient and central hubs of cellular lipid logistics. , 2017, Biochimica et biophysica acta. Molecular cell research.

[40]  Jacques Neefjes,et al.  Stop or Go? Endosome Positioning in the Establishment of Compartment Architecture, Dynamics, and Function. , 2017, Trends in cell biology.

[41]  C. Hetz,et al.  ER stress and the unfolded protein response in neurodegeneration , 2017, Nature Reviews Neurology.

[42]  E. Yeo,et al.  The role of ubiquitin-conjugating enzyme Ube2j1 phosphorylation and its degradation by proteasome during endoplasmic stress recovery , 2017, Journal of Cell Communication and Signaling.

[43]  M. Schuldiner,et al.  A Tether Is a Tether Is a Tether: Tethering at Membrane Contact Sites. , 2016, Developmental cell.

[44]  Ueli Aebi,et al.  Intermediate Filaments: Structure and Assembly. , 2016, Cold Spring Harbor perspectives in biology.

[45]  M. Peter,et al.  Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery , 2016, Nature Cell Biology.

[46]  Zhuo Gan,et al.  Vimentin Intermediate Filaments Template Microtubule Networks to Enhance Persistence in Cell Polarity and Directed Migration. , 2016, Cell systems.

[47]  N. Schwarz,et al.  Intermediate Filaments as Organizers of Cellular Space: How They Affect Mitochondrial Structure and Function , 2016, Cells.

[48]  J. Neefjes,et al.  An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport , 2016, Cell.

[49]  P. Morton,et al.  Folliculin directs the formation of a Rab34–RILP complex to control the nutrient‐dependent dynamic distribution of lysosomes , 2016, EMBO reports.

[50]  Valentin Jaumouillé,et al.  The position of lysosomes within the cell determines their luminal pH , 2016, The Journal of cell biology.

[51]  M. Varjosalo,et al.  Bidirectional Interplay between Vimentin Intermediate Filaments and Contractile Actin Stress Fibers. , 2015, Cell reports.

[52]  W. Prinz,et al.  Form follows function: the importance of endoplasmic reticulum shape. , 2015, Annual review of biochemistry.

[53]  Lin Guo,et al.  RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms , 2014, PLoS pathogens.

[54]  N. Ben-Tal,et al.  Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD , 2014, Molecular biology of the cell.

[55]  Uma Goyal,et al.  Untangling the web: mechanisms underlying ER network formation. , 2013, Biochimica et biophysica acta.

[56]  A. Sonnenberg,et al.  Nesprin-3 connects plectin and vimentin to the nuclear envelope of Sertoli cells but is not required for Sertoli cell function in spermatogenesis , 2013, Molecular biology of the cell.

[57]  S. Gygi,et al.  Why do cellular proteins linked to K63‐polyubiquitin chains not associate with proteasomes? , 2013, The EMBO journal.

[58]  M. Tagaya,et al.  Contribution of the long form of syntaxin 5 to the organization of the endoplasmic reticulum , 2012, Journal of Cell Science.

[59]  S. Ang,et al.  The role of secretory and endocytic pathways in the maintenance of cell polarity. , 2012, Essays in biochemistry.

[60]  P. Tyurin-Kuzmin,et al.  Vimentin intermediate filaments modulate the motility of mitochondria , 2011, Molecular biology of the cell.

[61]  J. Vicencio,et al.  Increased ER–mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress , 2011, Journal of Cell Science.

[62]  Cahir J. O'Kane,et al.  Lysosomal positioning coordinates cellular nutrient responses , 2011, Nature Cell Biology.

[63]  Yoko Shibata,et al.  Mechanisms Determining the Morphology of the Peripheral ER , 2010, Cell.

[64]  N. Hirokawa,et al.  Kinesin superfamily motor proteins and intracellular transport , 2009, Nature Reviews Molecular Cell Biology.

[65]  R. Goldman,et al.  The dynamic properties of intermediate filaments during organelle transport , 2009, Journal of Cell Science.

[66]  W. Zwart,et al.  Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning , 2009, The Journal of cell biology.

[67]  Keisuke Tanaka,et al.  p180 is involved in the interaction between the endoplasmic reticulum and microtubules through a novel microtubule-binding and bundling domain. , 2007, Molecular biology of the cell.

[68]  Bella Groisman,et al.  PERK-dependent compartmentalization of ERAD and unfolded protein response machineries during ER stress. , 2007, Experimental cell research.

[69]  M. Inagaki,et al.  Role of phosphorylation on the structural dynamics and function of types III and IV intermediate filaments. , 2007, Experimental cell research.

[70]  M. Omary,et al.  Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. , 2005, Trends in cell biology.

[71]  H. Hauri,et al.  Phosphorylation controls CLIMP-63-mediated anchoring of the endoplasmic reticulum to microtubules. , 2005, Molecular biology of the cell.

[72]  R. Kaufman,et al.  Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. , 2004, Journal of biochemistry.

[73]  E. Sztul,et al.  A novel type of regulation of the vimentin intermediate filament cytoskeleton by a Golgi protein. , 2002, European journal of cell biology.

[74]  Leann Tilley,et al.  Trafficking and assembly of the cytoadherence complex in Plasmodium falciparum‐infected human erythrocytes , 2001, The EMBO journal.

[75]  R. Kopito,et al.  Aggresomes: A Cellular Response to Misfolded Proteins , 1998, The Journal of cell biology.

[76]  H. Hauri,et al.  A novel direct interaction of endoplasmic reticulum with microtubules , 1998, The EMBO journal.

[77]  E. Reynolds.  THE USE OF LEAD CITRATE AT HIGH pH AS AN ELECTRON-OPAQUE STAIN IN ELECTRON MICROSCOPY , 1963, The Journal of cell biology.

[78]  T. Svitkina.  The Actin Cytoskeleton and Actin-Based Motility. , 2018, Cold Spring Harbor perspectives in biology.

[79]  G. Lederkremer,et al.  Compartmentalization of endoplasmic reticulum quality control and ER-associated degradation factors. , 2013, DNA and cell biology.

[80]  J. Ivaska.  Vimentin: Central hub in EMT induction? , 2011, Small GTPases.