Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy

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Abstract

Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they respond differentially to the stimulation of ER-phagy is unknown. Here, we describe an activation mechanism unique to FAM134C during starvation. In fed conditions, FAM134C is phosphorylated by casein kinase 2 (CK2) at critical residues flanking the LIR domain. Phosphorylation of these residues negatively affects binding affinity to the autophagy proteins LC3. During starvation, mTORC1 inhibition limits FAM134C phosphorylation by CK2, hence promoting receptor activation and ER-phagy. Using a novel tool to study ER-phagy in vivo and FAM134C knockout mice, we demonstrated the physiological relevance of FAM134C phosphorylation during starvation-induced ER-phagy in liver lipid metabolism. These data provide a mechanistic insight into ER-phagy regulation and an example of autophagy selectivity during starvation.

Abstract

The ER-phagy receptor FAM134C is regulated during starvation by CK2-mediated phosphorylation.

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Most cited references 60

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Mechanism and medical implications of mammalian autophagy

Zvulun Elazar, Ivan Dikic (2018)

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Improved side-chain torsion potentials for the Amber ff99SB protein force field

Kresten Lindorff-Larsen, Stefano Piana, Kim Palmo … (2010)

Recent advances in hardware and software have enabled increasingly long molecular dynamics (MD) simulations of biomolecules, exposing certain limitations in the accuracy of the force fields used for such simulations and spurring efforts to refine these force fields. Recent modifications to the Amber and CHARMM protein force fields, for example, have improved the backbone torsion potentials, remedying deficiencies in earlier versions. Here, we further advance simulation accuracy by improving the amino acid side-chain torsion potentials of the Amber ff99SB force field. First, we used simulations of model alpha-helical systems to identify the four residue types whose rotamer distribution differed the most from expectations based on Protein Data Bank statistics. Second, we optimized the side-chain torsion potentials of these residues to match new, high-level quantum-mechanical calculations. Finally, we used microsecond-timescale MD simulations in explicit solvent to validate the resulting force field against a large set of experimental NMR measurements that directly probe side-chain conformations. The new force field, which we have termed Amber ff99SB-ILDN, exhibits considerably better agreement with the NMR data. Proteins 2010. © 2010 Wiley-Liss, Inc.

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mTOR at the nexus of nutrition, growth, ageing and disease

Grace Y. Liu, David Sabatini (2020)

The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway’s central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.

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Author and article information

Contributors

Giorgia Di Lorenzo:

ORCID: https://orcid.org/0000-0001-8659-5268

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing

Francescopaolo Iavarone:

ORCID: https://orcid.org/0000-0002-8855-1848

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing

Marianna Maddaluno:

ORCID: https://orcid.org/0000-0002-7117-023X

Role: InvestigationRole: MethodologyRole: Validation

Ana Belén Plata-Gómez:

ORCID: https://orcid.org/0000-0002-6256-0084

Role: InvestigationRole: ResourcesRole: Writing - review & editing

Simone Aureli:

ORCID: https://orcid.org/0000-0002-4938-8603

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draft

Camila Paz Quezada Meza:

ORCID: https://orcid.org/0000-0002-3728-8779

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization

Laura Cinque:

ORCID: https://orcid.org/0000-0002-8497-3939

Role: Investigation

Alessandro Palma:

ORCID: https://orcid.org/0000-0003-1300-5479

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - review & editing

Alessio Reggio:

ORCID: https://orcid.org/0000-0001-5333-7502

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - review & editing

Carmine Cirillo:

ORCID: https://orcid.org/0000-0002-1639-7677

Role: Data curationRole: Formal analysisRole: Software

Francesca Sacco:

ORCID: https://orcid.org/0000-0001-5586-9529

Role: Formal analysisRole: MethodologyRole: ResourcesRole: Validation

Alexandra Stolz:

ORCID: https://orcid.org/0000-0002-3340-439X

Role: ConceptualizationRole: Formal analysis

Gennaro Napolitano:

ORCID: https://orcid.org/0000-0002-8615-4654

Role: Conceptualization

Oriano Marin:

ORCID: https://orcid.org/0000-0002-6175-4039

Role: MethodologyRole: Resources

Lorenzo A. Pinna:

ORCID: https://orcid.org/0000-0002-8856-4956

Role: ConceptualizationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Maria Ruzzene:

ORCID: https://orcid.org/0000-0001-8712-8151

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Vittorio Limongelli:

ORCID: https://orcid.org/0000-0002-4861-1199

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Alejo Efeyan:

ORCID: https://orcid.org/0000-0002-3806-6799

Role: ResourcesRole: Supervision

Paolo Grumati:

ORCID: https://orcid.org/0000-0002-9942-9389

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draft

Carmine Settembre:

ORCID: https://orcid.org/0000-0002-5829-8589

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - original draft

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: August 2022

Publication date (Electronic, pub): 31 August 2022

Volume: 8

Issue: 35

Electronic Location Identifier: eabo1215

Affiliations

[ ¹ ]Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.

[ ² ]Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

[ ³ ]Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Euler Institute, Lugano, Switzerland.

[ ⁴ ]Department of Biomedical Sciences, University of Padova, Padova, Italy.

[ ⁵ ]Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.

[ ⁶ ]Department of Biology, University of Rome “Tor Vergata”, Rome, Italy.

[ ⁷ ]Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany.

[ ⁸ ]Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Frankfurt am Main, Germany.

[ ⁹ ]Department of Translational Medicine, Federico II University, Naples, Italy.

[ ¹⁰ ]CNR Neuroscience Institute, Padova, Italy.

[ ¹¹ ]Department of Pharmacy, Federico II University, Naples, Italy.

Author notes

[* ]Corresponding author. Email: p.grumati@ 123456tigem.it (P.G.); settembre@ 123456tigem.it (C.S.)

[†]

These authors contributed equally to this work.

Author information

Giorgia Di Lorenzo https://orcid.org/0000-0001-8659-5268

Francescopaolo Iavarone https://orcid.org/0000-0002-8855-1848

Marianna Maddaluno https://orcid.org/0000-0002-7117-023X

Ana Belén Plata-Gómez https://orcid.org/0000-0002-6256-0084

Simone Aureli https://orcid.org/0000-0002-4938-8603

Camila Paz Quezada Meza https://orcid.org/0000-0002-3728-8779

Laura Cinque https://orcid.org/0000-0002-8497-3939

Alessandro Palma https://orcid.org/0000-0003-1300-5479

Alessio Reggio https://orcid.org/0000-0001-5333-7502

Carmine Cirillo https://orcid.org/0000-0002-1639-7677

Francesca Sacco https://orcid.org/0000-0001-5586-9529

Alexandra Stolz https://orcid.org/0000-0002-3340-439X

Gennaro Napolitano https://orcid.org/0000-0002-8615-4654

Oriano Marin https://orcid.org/0000-0002-6175-4039

Lorenzo A. Pinna https://orcid.org/0000-0002-8856-4956

Maria Ruzzene https://orcid.org/0000-0001-8712-8151

Vittorio Limongelli https://orcid.org/0000-0002-4861-1199

Alejo Efeyan https://orcid.org/0000-0002-3806-6799

Paolo Grumati https://orcid.org/0000-0002-9942-9389

Carmine Settembre https://orcid.org/0000-0002-5829-8589

Article

Publisher ID: abo1215

DOI: 10.1126/sciadv.abo1215

PMC ID: 9432840

PubMed ID: 36044577

SO-VID: e076b1e2-b8d7-467a-a8ee-68ce577faf32

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 14 January 2022

Date accepted : 20 July 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: SFB1177/2

Funded by: FundRef http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: WO210/20-2

Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;

Award ID: 714551

Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;

Award ID: 101001784

Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;

Award ID: 638891

Funded by: FundRef http://dx.doi.org/10.13039/501100002426, Fondazione Telethon;

Award ID: TMPGCBX16TT

Funded by: FundRef http://dx.doi.org/10.13039/501100004710, Fondazione Umberto Veronesi;

Funded by: MIUR-PRIN 2017;

Award ID: 2017FJZZRC

Funded by: Swiss National Supercomputing Center (CSCS);

Award ID: project ID u8

Funded by: FundRef http://dx.doi.org/10.13039/501100011033, Agencia Estatal de Investigación;

Award ID: BES-2017-081381

Funded by: RETOS projects Programme of Spanish Ministry of Science Innovation and Universities Spanish State Research Agency;

Award ID: SAF2015-67538-R

Funded by: RETOS projects Programme of Spanish Ministry of Science Innovation and Universities Spanish State Research Agency;

Award ID: PID2019-104012RB-I00

Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;

Award ID: 25407

Funded by: AFM Telethon (Trampoline Grant);

Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;

Award ID: MFAG-2020-24856

Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;

Award ID: IG 2015 Id 17717

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Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy

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European Respiratory Society: COVID-19

Most cited references 60

Mechanism and medical implications of mammalian autophagy

Improved side-chain torsion potentials for the Amber ff99SB protein force field

mTOR at the nexus of nutrition, growth, ageing and disease

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