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  • EMBO reports: 19 (9)

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TMEM41B is a novel regulator of autophagy and lipid mobilization

Francesca Moretti, Phil Bergman, Stacie Dodgson, David Marcellin, Isabelle Claerr, Jonathan M Goodwin, Rowena DeJesus, Zhao Kang, Christophe Antczak, Damien Begue, Debora Bonenfant, Alexandra Graff, Christel Genoud, John S Reece‐Hoyes, Carsten Russ, Zinger Yang, Gregory R Hoffman, Matthias Mueller, Leon O Murphy, Ramnik J Xavier, View ORCID ProfileBeat Nyfeler
DOI 10.15252/embr.201845889 | Published online 20.08.2018
EMBO reports (2018) 19, e45889
Francesca Moretti
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Phil Bergman
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Stacie Dodgson
Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
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David Marcellin
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Isabelle Claerr
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Jonathan M Goodwin
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Rowena DeJesus
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Zhao Kang
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Christophe Antczak
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Damien Begue
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Debora Bonenfant
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Alexandra Graff
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
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Christel Genoud
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
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John S Reece‐Hoyes
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Carsten Russ
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Zinger Yang
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Gregory R Hoffman
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Matthias Mueller
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Leon O Murphy
Novartis Institutes for BioMedical Research, Cambridge, MA, USA
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Ramnik J Xavier
Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
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Beat Nyfeler
Novartis Institutes for BioMedical Research, Basel, Switzerland
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Author Affiliations

  1. Francesca Moretti1,
  2. Phil Bergman2,
  3. Stacie Dodgson3,
  4. David Marcellin1,
  5. Isabelle Claerr1,
  6. Jonathan M Goodwin2,5,
  7. Rowena DeJesus2,
  8. Zhao Kang2,
  9. Christophe Antczak2,
  10. Damien Begue1,
  11. Debora Bonenfant1,
  12. Alexandra Graff4,
  13. Christel Genoud4,
  14. John S Reece‐Hoyes2,
  15. Carsten Russ2,
  16. Zinger Yang2,
  17. Gregory R Hoffman2,
  18. Matthias Mueller1,
  19. Leon O Murphy2,5,
  20. Ramnik J Xavier3 and
  21. Beat Nyfeler (beat.nyfeler{at}novartis.com)*,1
  1. 1Novartis Institutes for BioMedical Research, Basel, Switzerland
  2. 2Novartis Institutes for BioMedical Research, Cambridge, MA, USA
  3. 3Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
  4. 4Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
  5. 5Present Address: Casma Therapeutics, Cambridge, MA, USA
  1. ↵*Corresponding author. Tel: +41 792612693; E‐mail: beat.nyfeler{at}novartis.com
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Abstract

Autophagy maintains cellular homeostasis by targeting damaged organelles, pathogens, or misfolded protein aggregates for lysosomal degradation. The autophagic process is initiated by the formation of autophagosomes, which can selectively enclose cargo via autophagy cargo receptors. A machinery of well‐characterized autophagy‐related proteins orchestrates the biogenesis of autophagosomes; however, the origin of the required membranes is incompletely understood. Here, we have applied sensitized pooled CRISPR screens and identify the uncharacterized transmembrane protein TMEM41B as a novel regulator of autophagy. In the absence of TMEM41B, autophagosome biogenesis is stalled, LC3 accumulates at WIPI2‐ and DFCP1‐positive isolation membranes, and lysosomal flux of autophagy cargo receptors and intracellular bacteria is impaired. In addition to defective autophagy, TMEM41B knockout cells display significantly enlarged lipid droplets and reduced mobilization and β‐oxidation of fatty acids. Immunostaining and interaction proteomics data suggest that TMEM41B localizes to the endoplasmic reticulum (ER). Taken together, we propose that TMEM41B is a novel ER‐localized regulator of autophagosome biogenesis and lipid mobilization.

See also: E Morel & P Codogno (September 2018)

Synopsis

Embedded Image

Autophagy maintains cellular homeostasis by targeting damaged organelles, pathogens or misfolded proteins for lysosomal degradation. The ER transmembrane protein TMEM41B is a novel regulator of autophagosome biogenesis, lipid droplet homeostasis and mitochondrial respiration.

  • TMEM41B localizes to the endoplasmic reticulum.

  • Knockout of TMEM41B impairs autophagosome biogenesis and lysosomal delivery of cargo.

  • Absence of TMEM41B results in enlarged lipid droplets.

  • TMEM41B is required for mobilization and mitochondrial β‐oxidation of fatty acids.

  • autophagy
  • CRISPR
  • endoplasmic reticulum
  • lipid droplets
  • TMEM41B

EMBO Reports (2018) 19: e45889

  • Received February 1, 2018.
  • Revision received July 3, 2018.
  • Accepted July 12, 2018.
  • © 2018 Novartis Institute for Biomedical Research
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Volume 19, Issue 9
01 September 2018
EMBO reports: 19 (9)
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