A physical mechanism of TANGO1-mediated bulky cargo export
Abstract
The endoplasmic reticulum (ER)-resident protein TANGO1 assembles into a ring around ER exit sites (ERES), and links procollagens in the ER lumen to COPII machinery, tethers, and ER-Golgi intermediate compartment (ERGIC) in the cytoplasm (Raote et al., 2018). Here we present a theoretical approach to investigate the physical mechanisms of TANGO1 ring assembly and how COPII polymerization, membrane tension, and force facilitate the formation of a transport intermediate for procollagen export. Our results indicate that a TANGO1 ring, by acting as a linactant, stabilizes the open neck of a nascent COPII bud. Elongation of such a bud into a transport intermediate commensurate with bulky procollagens is then facilitated by two complementary mechanisms: (i) by relieving membrane tension, possibly by TANGO1-mediated fusion of retrograde ERGIC membranes; and (ii) by force application. Altogether, our theoretical approach identifies key biophysical events in TANGO1-driven procollagen export.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Government of Spain (Severo Ochoa" Programme (CEX2019-000910-S)")
- Morgan Chabanon
- Maria F Garcia-Parajo
- Felix Campelo
Spanish Government (BFU2013-44188-P)
- Ishier Raote
- Vivek Malhotra
Spanish Government (Consolider CSD2009-00016)
- Ishier Raote
- Vivek Malhotra
Spanish Government (Severo Ochoa Program SEV-2012-0208)
- Ishier Raote
- Vivek Malhotra
Spanish Government (Maria de Maeztu MDM-2015-0502)
- Vivek Malhotra
BIST (Ignite grant eTANGO)
- Ishier Raote
- Maria F Garcia-Parajo
- Vivek Malhotra
- Felix Campelo
Spanish Ministry of Science and Innovation (IJCI-2017-34751)
- Ishier Raote
Spanish Ministry of Science and Innovation (RYC-2017-22227)
- Felix Campelo
Europen Comission (CoG-681434)
- Nikhil Walani
- Marino Arroyo
Generalitat de Catalunya (2017-SGR-1278)
- Marino Arroyo
ICREA (ICREA academia)
- Marino Arroyo
Government of Spain (BFU2015-73288-JIN)
- Maria F Garcia-Parajo
- Felix Campelo
Spanish Government (Severo Ochoa Program,CEX2018-000797-S)
- Marino Arroyo
State Research Agency (PID2019-106232RB-I00/ 10.13039/501100011033)
- Morgan Chabanon
- Felix Campelo
Government of Spain (FIS2015-63550-R)
- Maria F Garcia-Parajo
- Felix Campelo
Government of Spain (FIS2017-89560-R)
- Morgan Chabanon
- Maria F Garcia-Parajo
- Felix Campelo
Fundacio Privada Cellex
- Morgan Chabanon
- Maria F Garcia-Parajo
- Felix Campelo
Fundacio Privada Mir-Puig
- Morgan Chabanon
- Maria F Garcia-Parajo
- Felix Campelo
Generalitat de Catalunya (CERCA program)
- Ishier Raote
- Morgan Chabanon
- Maria F Garcia-Parajo
- Vivek Malhotra
- Felix Campelo
European Comission (ERC Advanced Grant (GA 788546))
- Morgan Chabanon
- Maria F Garcia-Parajo
- Felix Campelo
LaserLab 4 Europe (GA 654148)
- Morgan Chabanon
- Maria F Garcia-Parajo
- Felix Campelo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jure Derganc, University of Ljubljana, Slovenia
Publication history
- Received: June 1, 2020
- Accepted: November 9, 2020
- Accepted Manuscript published: November 10, 2020 (version 1)
- Version of Record published: November 30, 2020 (version 2)
Copyright
© 2020, Raote et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,567
- Page views
-
- 248
- Downloads
-
- 13
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-b/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis.
-
- Cell Biology
- Neuroscience
Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.